RADIOLABELLED COMPOUND OF A QUATERNARY AMMONIUM SALT OF A POLYCYCLIC AROMATIC AMINE AND METHODS OF MANUFACTURING AND DIAGNOSTIC USE THEREOF

Abstract

The disclosure relates to a radioisotope-labelled compound having a structure according to formula I, wherein a wavy line indicates a single bond between a non-nodal carbon atom of a polycyclic aromatic system and an R.sup.1 substituent selected from a hydrogen; a halogen; a hydroxy; a protected hydroxy; a C.sub.1-4 alkoxy; a nitro group; an amino group; an amino group having 1 hydrogen replaced with a C.sub.1-C.sub.6 alkyl group; an amino group having 2 hydrogens replaced with a C.sub.1-C.sub.6 alkyl group; an amino group having 2 hydrogen atoms replaced with C.sub.2-5 alkylene to form a heterocyclic ring; a chain C.sub.1-6 carbon group; a chain C.sub.1-6 carbon group having a substituent selected from a halogen, carboxyl, a formyl, and a C.sub.1-4 alkanesulfonic; a phenyl group; a phenyl group having 1-5 substituents independently selected from halogens, a chain C.sub.1-6 carbon, a halogenated chain C.sub.1-6 carbon substituent, a hydroxy, a protected hydroxy, a C.sub.1-4 alkoxy, and an amino group having 1-2 atoms of hydrogen replaced with C.sub.1-6 alkyl; wherein R.sup.2 is a chain aliphatic substituent having: a total of 1-16 carbon atoms, an atom of .sup.18F fluorine radioisotope replacing a hydrogen atom at one of the carbon atoms, and a —CH.sub.2 fragment as a terminal member of a chain, wherein the chain connects to one of a hydrogen, a phenyl group, and a phenyl group having 1-3 substituents selected from halogens and C.sub.1-6 alkyl, and wherein if the chain contains at least 2 carbon atoms and there is a bivalent link between the chain carbon atoms, then the bivalent link is selected from the group consisting of an oxygen atom —O—, a sulfur atom —S—, and a C.sub.3-6 cycloalkylene; wherein R.sup.3 and R.sup.4 are combined to form a bivalent butadienyl-1,3 substituent whose terminal carbon atoms are linked to adjacent non-nodal carbon atoms of a B ring to form an aromatic C ring fused with an A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms; wherein n is an integer of 9; wherein X.sup.− is a pharmaceutically acceptable counter ion selected from: an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid, a hydrate thereof, and a solvate thereof.

##STR00001##

Claims

1. A radioisotope-labelled compound comprising a quaternary ammonium salt of a polycyclic aromatic amine having a structure according to formula I, ##STR00007## wherein a wavy line indicates a single bond between a non-nodal carbon atom of a polycyclic aromatic system and an R.sup.1 substituent, wherein the R.sup.1 substituent selected from: a hydrogen; a halogen; a hydroxy; a protected hydroxy; a C.sub.1-4 alkoxy; a nitro group; an amino group; an amino group having 1 hydrogen replaced with a C.sub.1-C.sub.6 alkyl group; an amino group having 2 hydrogens replaced with a C.sub.1-C.sub.6 alkyl group; an amino group having 2 hydrogen atoms replaced with C.sub.2-5 alkylene to form a heterocyclic ring; a chain C.sub.1-6 carbon group; a chain C.sub.1-6 carbon group having a substituent selected from a halogen, carboxyl, a formyl, and a C.sub.1-4 alkanesulfonic; a phenyl group; a phenyl group having 1-5 substituents independently selected from halogens, a chain C.sub.1-6 carbon, a halogenated chain C.sub.1-6 carbon substituent, a hydroxy, a protected hydroxy, a C.sub.1-4 alkoxy, and an amino group having 1-2 atoms of hydrogen replaced with C.sub.1-6 alkyl; wherein R.sup.2 is a chain aliphatic substituent having: a total of 1-16 carbon atoms, an atom of .sup.18F fluorine radioisotope replacing a hydrogen atom at one of the carbon atoms, and a —CH.sub.2 fragment as a terminal member of a chain, wherein the chain connects to one of a hydrogen, a phenyl group, and a phenyl group having 1-3 substituents selected from halogens and C.sub.1-6 alkyl, and wherein if the chain contains at least 2 carbon atoms and there is a bivalent link between the chain carbon atoms, then the bivalent link is selected from the group consisting of an oxygen atom —O—, a sulfur atom —S—, and a C.sub.3-6 cycloalkylene; wherein R.sup.3 and R.sup.4 are combined to form a bivalent butadienyl-1,3 substituent whose terminal carbon atoms are linked to adjacent non-nodal carbon atoms of a B ring to form an aromatic C ring fused with an A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms; wherein n is an integer of 9; wherein X.sup.− is a pharmaceutically acceptable counter ion selected from: an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid, a hydrate thereof, and a solvate thereof.

2. The radioisotope-labelled compound according to claim 1, wherein the R.sup.1 substituent is selected from: the hydrogen; the halogen; the C.sub.1-4 alkoxy; the nitro group; the amino group; an amino group having 1 hydrogen replaced with a C.sub.1-C.sub.4 alkyl group; an amino group having 2 hydrogens replaced with the C.sub.1-C.sub.4 alkyl group; a chain C.sub.1-4 carbon group; a chain C.sub.1-4 carbon group having a substituent selected from the halogen and a C.sub.1-4 alkanesulfonic; a phenyl group; a phenyl group having 1-3 substituents independently selected from halogens, a chain C.sub.1-4 carbon, a halogenated chain C.sub.1-4 carbon substituent, the C.sub.1-4 alkoxy, and the amino group having 1-2 atoms of hydrogen replaced with C.sub.1-4 alkyl; and wherein for R.sup.2, if the chain contains at least 2 carbon atoms and there is a bivalent link between the chain carbon atoms, then the link is selected from the group consisting of the oxygen atom —O— and the sulfur atom —S—.

3. The radioisotope-labelled compound according to claim 2, wherein the R.sup.1 substituent is selected from: the hydrogen; the halogen; the C.sub.1-4 alkoxy; the amino group; the amino group having 1 hydrogen replaced with the C.sub.1-C.sub.4 alkyl group; the amino group having 2 hydrogens replaced with the C.sub.1-C.sub.4 alkyl group; the chain C.sub.1-4 carbon group; the chain C.sub.1-4 carbon group having a substituent selected from the halogen, the phenyl group; the phenyl group having 1-3 substituents independently selected from halogens, the chain C.sub.1-4 carbon, the halogenated chain C.sub.1-4 carbon substituent, and the C.sub.1-4 alkoxy; and wherein for R.sup.2, if the chain contains at least 2 carbon atoms and there is a bivalent link between the chain carbon atoms, then the link is the oxygen atom —O—.

4. The radioisotope-labelled compound according to claim 3, wherein R.sup.1 substituent is selected from: the hydrogen; the halogen; the C.sub.1-4 alkoxy; the amino group; the amino group having 1 hydrogen replaced with a C.sub.1-C.sub.2 alkyl group; the amino group having 2 hydrogens replaced with the C.sub.1-C.sub.2 alkyl group; the chain C.sub.1-4 carbon group; the chain C.sub.1-4 carbon group having a substituent selected from the halogen, the phenyl group; the phenyl group having 1-3 substituents independently selected from halogens, the chain C.sub.1-4 carbon, and the halogenated chain C.sub.1-4 carbon substituent; and wherein for R.sup.2, the bivalent link between the chain carbon atoms is absent, and the chain connects to one of a hydrogen, a phenyl group, and a phenyl group having 1-3 substituents selected from halogens and C.sub.1-4 alkyl.

5. The radioisotope-labelled compound according to claim 4, wherein the R.sup.1 substituent is selected from: the hydrogen; the halogen; the amino group; the amino group having 1 hydrogen replaced with the C.sub.1-C.sub.2 alkyl group; the amino group having 2 hydrogens replaced with the C.sub.1-C.sub.2 alkyl group; the chain C.sub.1-4 carbon group; the phenyl group; the phenyl group having 1-3 substituents independently selected from halogens, the chain C.sub.1-4 carbon, and the halogenated chain C.sub.1-4 carbon substituent wherein for R.sup.2, the chain connects to one of a hydrogen, a phenyl group, and a phenyl group having 1-3 substituents selected from the halogens.

6. A positron emission tomography diagnostic method, the method comprising: (a) administering a radioisotope-labelled compound to a subject; and (b) performing a positron emission tomography scan on the subject, wherein the radioisotope-labelled compound comprises: the radioisotope-labelled compound comprising a quaternary ammonium salt of a polycyclic aromatic amine having a structure according to formula I: ##STR00008## wherein a wavy line indicates a single bond between the non-nodal carbon atom of a polycyclic aromatic system and an R.sup.1 substituent, wherein the R.sup.1 is a substituent selected from: a hydrogen; a halogen; a hydroxyl; a protected hydroxyl; a C.sub.1-4 alkoxy; a nitro group; an amino group having 1 hydrogen atom replaced with C.sub.1-6 alkyl group; an amino group having 2 hydrogen atoms replaced with C.sub.1-6 alkyl group; an amino group having 2 hydrogen atoms replaced with C.sub.2-5 alkylene to form a heterocyclic ring; a chain C.sub.1-6 carbon group; a chain C.sub.1-6 carbon group having a substituent selected from a halogen, a carboxyl, a formyl, and a C.sub.1-4 alkanesulfonic; a phenyl group; a phenyl group having 1-5 substituents independently selected from halogens, a chain C.sub.1-6 carbon, a halogenated chain C.sub.1-6 carbon substituent, a hydroxy, a protected hydroxy, a C.sub.1-4 alkoxy, and an amino group having 1-2 atoms of hydrogen replaced with C.sub.1-6 alkyl; wherein R.sup.2 is a chain aliphatic substituent having: a total of 1-16 carbon atoms, an atom of .sup.18F fluorine radioisotope replacing a hydrogen atom at one of the carbon atoms, and a —CH.sub.2 fragment as a terminal member of a chain, wherein the chain connects to one of a hydrogen, a phenyl group, and a phenyl group having 1-3 substituents selected from halogens and C.sub.1-6 alkyl, and wherein if the chain contains at least 2 carbon atoms and there is a bivalent link between the chain carbon atoms, then the bivalent link is selected from the group consisting of an oxygen atom —O—, a sulfur atom —S—, and a C.sub.3-6 cycloalkylene; wherein R.sup.3 and R.sup.4 are combined to form a bivalent butadienyl-1,3 substituent whose terminal carbon atoms are linked to adjacent non-nodal carbon atoms of a B ring to form an aromatic C ring fused with an A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms; wherein n is an integer of 9; wherein X.sup.− is a pharmaceutically acceptable counter ion selected from: an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid, a hydrate thereof, and a solvate thereof.

7. The positron emission tomography diagnostic method according to claim 6, further comprising examining the cardiovascular system of the subject, and wherein the subject is a mammal.

8. The positron emission tomography diagnostic method according to claim 6, further comprising testing a myocardial perfusion of a myocardium of the subject to quantify a regional blood flow.

9. The positron emission tomography diagnostic method according to claim 8, further comprising quantifying a coronary reserve of the subject.

10. A pharmaceutical composition comprising: a pharmaceutically acceptable carrier or diluent; and a radioisotope-labelled compound comprising a quaternary ammonium salt of a polycyclic aromatic amine having a structure according to formula I ##STR00009## wherein a wavy line indicates a single bond between a non-nodal carbon atom of a polycyclic aromatic system and an R.sup.1 substituent, wherein the R.sup.1 substituent is selected from: a hydrogen; a halogen; a hydroxy; a protected hydroxyl; C.sub.1-4 alkoxy; a nitro group; an amino group having 1 hydrogen atom replaced with C.sub.1-6 alkyl group; an amino group having 2 hydrogen atoms replaced with C.sub.1-6 alkyl group; an amino group having 2 hydrogen atoms replaced with C.sub.2-5 alkylene to form a heterocyclic ring; a chain C.sub.1-6 carbon group; a chain C.sub.1-6 carbon group having a substituent selected from a halogen, carboxyl, a formyl, and a C.sub.1-4 alkanesulfonic; a phenyl group; a phenyl group having 1-5 substituents independently selected from halogens, a chain C.sub.1-6 carbon, a halogenated chain C.sub.1-6 carbon substituent, a hydroxy, a protected hydroxy, a C.sub.1-4 alkoxy, and an amino group having 1-2 atoms of hydrogen replaced with C.sub.1-6 alkyl; wherein R.sup.2 is a chain aliphatic substituent having: a total of 1-16 carbon atoms, an atom of .sup.18F fluorine radioisotope replacing a hydrogen atom at one of the carbon atoms, and a —CH.sub.2 fragment as a terminal member of a chain, wherein the chain connects to one of a hydrogen, a phenyl group, and a phenyl group having 1-3 substituents selected from halogens and C.sub.1-6 alkyl, and wherein if the chain contains at least 2 carbon atoms and there is a bivalent link between the chain carbon atoms, then the bivalent link is selected from the group consisting of an oxygen atom —O—, a sulfur atom —S—, and a C.sub.3-6 cycloalkylene; wherein R.sup.3 and R.sup.4 are combined to form a bivalent butadienyl-1,3 substituent whose terminal carbon atoms are linked to adjacent non-nodal carbon atoms of a B ring to form an aromatic C ring fused with on A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms, wherein n is an integer of 9; wherein X.sup.− is a pharmaceutically acceptable counter ion selected from: an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid, a hydrate thereof, and a solvate thereof.

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is formulated as a sterile solution.

12. The pharmaceutical composition according to claim 10, wherein the R.sup.1 substituent is selected from: the hydrogen; the halogen; the C.sub.1-4 alkoxy; the nitro group; the amino group; an amino group having 1 hydrogen replaced with a C.sub.1-C.sub.4 alkyl group; an amino group having 2 hydrogens replaced with the C.sub.1-C.sub.4 alkyl group; a chain C.sub.1-4 carbon group; a chain C.sub.1-4 carbon group having a substituent selected from the halogen and a C.sub.1-4 alkanesulfonic; a phenyl group; a phenyl group having 1-3 substituents independently selected from halogens, a chain C.sub.1-4 carbon, a halogenated chain C.sub.1-4 carbon substituent, the C.sub.1-4 alkoxy, and the amino group having 1-2 atoms of hydrogen replaced with C.sub.1-4 alkyl; and wherein for R.sup.2, if the chain contains at least 2 carbon atoms and there is a bivalent link between the chain carbon atoms, then the link is selected from the group consisting of the oxygen atom —O— and the sulfur atom —S—.

13. The pharmaceutical composition according to claim 12, wherein the R.sup.1 substituent is selected from: the hydrogen; the halogen; the C.sub.1-4 alkoxy; the amino group; the amino group having 1 hydrogen replaced with the C.sub.1-C.sub.4 alkyl group; the amino group having 2 hydrogens replaced with the C.sub.1-C.sub.4 alkyl group; the chain C.sub.1-4 carbon group; the chain C.sub.1-4 carbon group having a substituent selected from the halogen, the phenyl group; the phenyl group having 1-3 substituents independently selected from halogens, the chain C.sub.1-4 carbon, the halogenated chain C.sub.1-4 carbon substituent, and the C.sub.1-4 alkoxy; and wherein for R.sup.2, if the chain contains at least 2 carbon atoms and there is the bivalent link between the chain carbon atoms, then the link is the oxygen atom —O—.

14. The pharmaceutical composition according to claim 13, wherein R.sup.1 substituent is selected from: the hydrogen; the halogen; the C.sub.1-4 alkoxy; the amino group; an amino group having 1 hydrogen replaced with a C.sub.1-C.sub.2 alkyl group; an amino group having 2 hydrogens replaced with the C.sub.1-C.sub.2 alkyl group; the chain C.sub.1-4 carbon group; the chain C.sub.1-4 carbon group having a substituent selected from the halogen, the phenyl group; the phenyl group having 1-3 substituents independently selected from halogens, the chain C.sub.1-4 carbon, and the halogenated chain C.sub.1-4 carbon substituent; and wherein for R.sup.2, wherein for R.sup.2, the bivalent link between the chain carbon atoms is absent, and the chain connects to one of a hydrogen, a phenyl group, and a phenyl group having 1-3 substituents selected from halogens and C.sub.1-4 alkyl.

15. The pharmaceutical composition according to claim 14, wherein the R.sup.1 substituent is selected from: the hydrogen; the halogen; the amino group; the amino group having 1 hydrogen replaced with the C.sub.1-C.sub.2 alkyl group; the amino group having 2 hydrogens replaced with the C.sub.1-C.sub.2 alkyl group; the chain C.sub.1-4 carbon group; the phenyl group; the phenyl group having 1-3 substituents independently selected from halogens, the chain C.sub.1-4 carbon, and the halogenated chain C.sub.1-4 carbon substituent, wherein for R.sup.2, the chain connects to one of a hydrogen, a phenyl group, and a phenyl group having 1-3 substituents selected from halogens.

16. A method for manufacturing a pharmaceutical composition, the method comprising combining a pharmaceutically acceptable carrier with a radioisotope-labelled compound, wherein the radioisotope-labelled compound comprises: a quaternary ammonium salt of a polycyclic aromatic amine having a structure according to formula I: ##STR00010## wherein a wavy line indicates a single bond between a non-nodal carbon atom of a polycyclic aromatic system and an R.sup.1 substituent; wherein the R.sup.1 substituent is selected from: a hydrogen; a halogen; a hydroxy; a protected hydroxy; a C.sub.1-4 alkoxy; a nitro group; an amino group; an amino group having 1 hydrogen replaced with a C.sub.1-C.sub.6 alkyl group; an amino group having 2 hydrogens replaced with a C.sub.1-C.sub.6 alkyl group; an amino group having 2 hydrogen atoms replaced with C.sub.2-5 alkylene to form a heterocyclic ring; a chain C.sub.1-6 carbon group; a chain C.sub.1-6 carbon group having a substituent selected from a halogen, carboxyl, a formyl, and a C.sub.1-4 alkanesulfonic; a phenyl group; a phenyl group having 1-5 substituents independently selected from halogens, a chain C.sub.1-6 carbon, a halogenated chain C.sub.1-6 carbon substituent, a hydroxy, a protected hydroxy, a C.sub.1-4 alkoxy, and an amino group having 1-2 atoms of hydrogen replaced with C.sub.1-6 alkyl; wherein R.sup.2 is a chain aliphatic substituent having: a total of 1-16 carbon atoms, an atom of .sup.18F fluorine radioisotope replacing a hydrogen atom at one of the carbon atoms, and a —CH.sub.2 fragment as a terminal member of a chain, wherein the chain connects to one of a hydrogen, a phenyl group, and a phenyl group having 1-3 substituents selected from halogens and C.sub.1-6 alkyl, and wherein if the chain contains at least 2 carbon atoms and there is a bivalent link between the chain carbon atoms, then the bivalent link is selected from the group consisting of an oxygen atom —O—, a sulfur atom —S—, and a C.sub.3-6 cycloalkylene; wherein R.sup.3 and R.sup.4 are combined to form a bivalent butadienyl-1,3 substituent whose terminal carbon atoms are linked to adjacent non-nodal carbon atoms of a B ring to form an aromatic C ring fused with an A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms; wherein n is an integer of 9; wherein X.sup.− is a pharmaceutically acceptable counter ion selected from: an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid, a hydrate thereof, and a solvate thereof.

17. The method for manufacturing a pharmaceutical composition according to claim 16, further comprising sterilizing the pharmaceutical composition to form a sterile solution.

Description

DETAILED DESCRIPTION

[0015] The object of the disclosure is to provide a radioisotope-labelled compound of quaternary ammonium salt of a polycyclic aromatic amine, the use of the radioisotope-labelled compound of quaternary ammonium salt of a polycyclic aromatic amine in a diagnostic method of positron emission tomography, and to provide a pharmaceutical composition containing said radioisotope-labelled compound of quaternary ammonium salt of a polycyclic aromatic amine.

[0016] The disclosure relates to a radioisotope-labelled compound of quaternary ammonium salt of a polycyclic aromatic amine with formula I,

##STR00003##

in which formula I

[0017] the wavy line indicates a single bond between the non-nodal carbon atom of a polycyclic aromatic system and the R.sup.1 substituent,

[0018] R.sup.1 is a substituent independently selected from hydrogen, halogens, a hydroxy optionally protected, C.sub.1-4 alkoxy, a nitro group, an amino group optionally having 1 or 2 hydrogen atoms replaced with C.sub.1-6 alkyl or having 2 hydrogen atoms replaced with C.sub.2-5 alkylene to form a heterocyclic ring, a chain C.sub.1-6 carbon group optionally having a halogen, carboxyl, formyl or C.sub.1-4 alkanesulfonic substituent, and a phenyl group optionally having 1-5 substituents independently selected from halogens, a chain C.sub.1-6 carbon substituent, a halogenated chain C.sub.1-6 carbon substituent, a hydroxy optionally protected, C.sub.1-4 alkoxy, an amino group optionally having 1-2 hydrogen atoms replaced with C.sub.1-6 alkyl,

[0019] R.sup.2 is a chain aliphatic substituent having the —CH.sub.2— fragment as the terminal member of the chain, to which chain a phenyl group is optionally attached optionally having 1-3 substituents selected from halogens and C.sub.1-6 alkyl, and, if the chain contains at least 2 carbon atoms, in which chain there is optionally a bivalent link between the chain carbon atoms, said link selected from the oxygen atom —O—, sulfur atom —S— and C.sub.3-6 cycloalkylene, wherein the R.sup.2 substituent contains a total of 1-16 carbon atoms, and the hydrogen atom at one of the carbon atoms is replaced with an atom of .sup.18F fluorine radioisotope,

[0020] R.sup.3 and R.sup.4 are combined to form a bivalent butadienyl-1,3 substituent whose terminal carbon atoms are linked to the adjacent non-nodal carbon atoms of the B ring to form an aromatic C ring fused with the A and B ring system, having R substituents at non-nodal carbon atoms,

[0021] n is an integer of 9,

[0022] X.sup.− is a pharmaceutically acceptable counterion, which is an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid, or a hydrate or solvate thereof.

[0023] Preferably, the disclosure relates to a compound with formula I, wherein the wavy line indicates a single bond between the non-nodal carbon atom of a polycyclic aromatic system and the R.sup.1 substituent,

[0024] R.sup.1 is a substituent independently selected from hydrogen, halogens, C.sub.1-4 alkoxy, a nitro group, an amino group optionally having 1 or 2 hydrogen atoms replaced with C.sub.1-4 alkyl, a chain C.sub.1-6 carbon group optionally having a halogen or C.sub.1-4 alkanesulfonic substituent, and a phenyl group optionally having 1-3 substituents independently selected from halogens, a chain C.sub.1-4 carbon substituent, a halogenated chain C.sub.1-4 carbon substituent, C.sub.1 4 alkoxy, an amino group optionally having 1-2 atoms of hydrogen replaced with C.sub.1-4 alkyl,

[0025] R.sup.2 is a chain aliphatic substituent having the —CH.sub.2— fragment as the terminal member of the chain, to which chain a phenyl group is optionally attached optionally having 1-3 substituents selected from halogens and C1-6 alkyl, and, if the chain contains at least 2 carbon atoms, in which chain there is optionally a bivalent link between the carbon atoms, said link selected from the oxygen atom —O— and sulfur atom —S—, wherein the R.sup.2 substituent contains a total of 1-16 carbon atoms, and the hydrogen atom at one of the carbon atoms is replaced with an atom of .sup.18F fluorine radioisotope,

[0026] R.sup.3 and R.sup.4 are combined to form a butadienyl-1,3 substituent whose terminal carbon atoms are linked to the adjacent non-nodal carbon atoms of the B ring to form an aromatic C ring fused with the A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms,

[0027] n is an integer of 9,

[0028] X.sup.− is a pharmaceutically acceptable counterion, which is an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid, or a hydrate or solvate thereof.

[0029] The disclosure relates in particular to a compound with formula I, wherein the wavy line indicates a single bond between the non-nodal carbon atom of a polycyclic aromatic system and the R.sup.1 substituent,

[0030] R.sup.1 is a substituent independently selected from hydrogen, halogens, C.sub.1-4 alkoxy, an amino group optionally having 1-2 hydrogen atoms replaced with C.sub.1-4 alkyl, a chain C.sub.1-4 carbon group optionally having a halogen substituent, and a phenyl group optionally having 1-3 substituents independently selected from halogens, a chain C.sub.1-4 carbon substituent, a halogenated chain C.sub.1-4 carbon substituent, C.sub.1-4 alkoxy,

[0031] R.sup.2 is a chain aliphatic substituent having the —CH.sub.2— fragment as the terminal member of the chain, to which chain a phenyl group is optionally attached optionally having 1-3 substituents selected from halogens and C.sub.1-6 alkyl, and, if the chain contains at least 2 carbon atoms, in which chain there is optionally a bivalent link between the carbon atoms, said link being the oxygen atom —O—, wherein the R.sup.2 substituent contains a total of 1-16 carbon atoms, and the hydrogen atom at one of the carbon atoms is replaced with an atom of .sup.18F fluorine radioisotope,

[0032] R.sup.3 and R.sup.4 are combined to form a butadienyl-1,3 substituent whose terminal carbon atoms are linked to the adjacent non-nodal carbon atoms of the B ring to form an aromatic C ring fused with the A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms,

[0033] n is an integer of 9,

[0034] X.sup.− is a pharmaceutically acceptable counterion, which is an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid,

[0035] or a hydrate or solvate.

[0036] The disclosure relates especially to a compound with formula I, wherein the wavy line indicates a single bond between the non-nodal carbon atom of a polycyclic aromatic system and the R.sup.1 substituent,

[0037] R.sup.1 is a substituent independently selected from hydrogen, halogens, C.sub.1-4 alkoxy, an amino group optionally having 1-2 hydrogen atoms replaced with C.sub.1-2 alkyl, a chain C.sub.1-4 carbon group optionally having a halogen substituent, and a phenyl group optionally having 1-3 substituents independently selected from halogens, a chain C.sub.1-4 carbon substituent and a halogenated chain C.sub.1-4 carbon substituent,

[0038] R.sup.2 is a chain aliphatic substituent having the —CH.sub.2— fragment as the terminal member of the chain, to which chain a phenyl group is optionally attached, optionally having 1-3 substituents selected from halogens and C.sub.1-4 alkyl, wherein the R.sup.2 substituent contains a total of 1-16 carbon atoms, and the hydrogen atom at one of the carbon atoms is replaced with an atom of .sup.18F fluorine radioisotope,

[0039] R.sup.3 and R.sup.4 are combined to form a butadienyl-1,3 substituent whose terminal carbon atoms are linked to the adjacent non-nodal carbon atoms of the B ring to form an aromatic C ring fused with the A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms,

[0040] n is an integer of 9,

[0041] X.sup.− is a pharmaceutically acceptable counterion, which is an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid, or a hydrate or solvate thereof.

[0042] Particularly preferably, the disclosure relates to a compound with formula I, wherein the wavy line indicates a single bond between the non-nodal carbon atom of a polycyclic aromatic system and the R.sup.1 substituent,

[0043] R.sup.1 is a substituent independently selected from hydrogen, halogens, an amino group optionally having 1-2 hydrogen atoms replaced with C.sub.1-2 alkyl, a chain C.sub.1-4 carbon group, and a phenyl group optionally having 1-3 substituents independently selected from a chain C.sub.1-4 carbon substituent and a halogenated chain C.sub.1-4 carbon substituent,

[0044] R.sup.2 is a chain aliphatic substituent having the —CH.sub.2— fragment as the terminal member of the chain, to which chain a phenyl group is optionally attached optionally having a halogen substituent, wherein the R.sup.2 substituent contains a total of 1-16 carbon atoms, and the hydrogen atom at one of the carbon atoms is replaced with an atom of .sup.18F fluorine radioisotope,

[0045] R.sup.3 and R.sup.4 are combined to form a butadienyl-1,3 substituent whose terminal carbon atoms are linked to the adjacent non-nodal carbon atoms of the B ring to form an aromatic C ring fused with the A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms,

[0046] n is an integer of 9,

[0047] X.sup.− is a pharmaceutically acceptable counterion, which is an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid,

[0048] or a hydrate or solvate thereof.

[0049] The disclosure relates to a radioisotope-labelled compound as defined above for use in a diagnostic method of positron emission tomography. Preferably, said diagnostic method is used for the examination of the cardiovascular system in a mammal. Said diagnostic method includes a myocardial perfusion imaging for quantifying regional blood flow through the myocardium and/or a cardiac perfusion test to quantify the coronary reserve in coronary artery disease.

[0050] The disclosure also relates to a pharmaceutical composition containing a radioisotope-labelled compound specified above and a pharmaceutically acceptable carrier or diluent. Preferably, said composition is in the form of a sterile solution.

[0051] The radioisotope-labelled compound is used for the manufacture of an agent for use in a diagnostic method of positron emission tomography. Preferably, the diagnostic method is used for the examination of the cardiovascular system in a mammal. The diagnostic method is used, in particular, for testing cardiac perfusion for quantifying regional blood flow through the myocardium and/or for quantifying the coronary reserve in coronary artery disease.

[0052] The disclosure provides a .sup.18F-radiolabelled compound for use as a cardiotracer to evaluate myocardial perfusion and diagnose coronary artery disease during a PET scan. Use of a cardiotracer containing the .sup.18F radionuclide, for which the range of positrons of the order of 0.6 mm, allows for obtaining a higher spatial resolution of images acquired during the scan and a higher counting sensitivity compared to other PET tracers, such as .sup.82Rb, where the range of positrons is 5.9 mm or (1.6 mm), since the spatial resolution increases as the kinetic energy of positrons decreases. The use of PET technology and of the cardiotracer according to the disclosure allows for quantifying myocardial blood flow in absolute values including the estimation of the flow through each coronary artery, without the need for invasive catheterisation thereof. Where cardiac perfusion in a PET test is assessed using tracers containing short half-life radionuclides, cardiac perfusion imaging can only be performed in a PET lab with direct access to a cyclotron or generator, since the tracer activity would usually undergo total decay during the time needed for transport to a remote PET lab. Delivery of a cardiotracer in the form of the compound according to the disclosure labelled with the .sup.18Fradionuclide, with a half-life of 109.8 ruin, allows for producing a cardiotracer outside the PET laboratory and, if necessary, for delivering the pharmaceutical form prepared to the place of testing.

[0053] Effective and readily accessible cardiological diagnostics using PET is paramount, because, in addition to contributing to understanding the pathophysiology of heart failure, it provides a tool to assess the outcome of pharmacological and invasive treatment. Apart from the data on organ function (perfusion, metabolism and left ventricular function), the PET-CT method provides quantitative data on the significance of anatomical stenoses in coronary arteries. Both tests, when performed simultaneously, provide a comprehensive diagnostic and prognostic method for the evaluation of patients with chronic heart failure of ischemic aetiology.

[0054] The disclosure is described in detail with reference to the drawing, in which FIG. 1 shows representative PET images of radioactivity distribution obtained in the study on rats following the administration of the pharmaceutical form of 5-(2-[.sup.18F]fluoroethyl)phenanthridinium salt, FIG. 2 shows representative PET images of radioactivity distribution obtained in the study on rats following the administration of the pharmaceutical form of 6-phenyl-5-(2-[.sup.18F]fluoroethyl)-phenanthridinium salt, and FIG. 3 shows representative PET images obtained in the study on rats following the administration of the pharmaceutical form of 3,6-bis(dimethylamino)-10-(2-[.sup.18F]fluoroethyl)acridinium salt.

[0055] The disclosure relates to a radioisotope-labelled compound of quaternary ammonium salt of a polycyclic aromatic amine with formula I,

##STR00004##

in which formula I

[0056] the wavy line indicates a single bond between the non-nodal carbon atom of a polycyclic aromatic system and the R.sup.1 substituent,

[0057] R.sup.1 is a substituent independently selected from hydrogen, halogens, a hydroxy optionally protected, C.sub.1-4 alkoxy, a nitro group, an amino group optionally having 1 or 2 hydrogen atoms replaced with C.sub.1-6 alkyl or having 2 hydrogen atoms replaced with C.sub.2-5 alkylene to form a heterocyclic ring, a chain C.sub.1-6 carbon group optionally having a halogen, carboxy, formyl or C.sub.1-4 alkanesulfonic substituent, and a phenyl group optionally having 1-5 substituents independently selected from halogens, a chain C.sub.1-6 carbon, a halogenated chain C.sub.1-6 carbon substituent, a hydroxy optionally protected, C.sub.1-4 alkoxy, an amino group optionally having 1-2 hydrogen atoms replaced with C.sub.1-6 alkyl,

[0058] R.sup.2 is a chain aliphatic substituent having the —CH.sub.2— fragment as the terminal member of the chain, to which chain a phenyl group is optionally attached optionally having 1-3 substituents selected from halogens and C.sub.1-6 alkyl, and, if the chain contains at least 2 carbon atoms, in which chain there is optionally a bivalent link between the chain carbon atoms, said link selected from the oxygen atom —O—, sulfur atom —S— and C.sub.3-6 cycloalkylene, wherein the R.sup.2 substituent contains a total of 1-16 carbon atoms, and the hydrogen atom at one of the carbon atoms is replaced with an atom of .sup.18F fluorine radioisotope,

[0059] R.sup.3 and R.sup.4 are combined to form a bivalent butadienyl-1,3 substituent whose terminal carbon atoms are linked to the adjacent non-nodal carbon atoms of the B ring to form an aromatic C ring fused with the A and B ring system, having IV substituents at non-nodal carbon atoms,

n is an integer of 9,
X.sup.− is a pharmaceutically acceptable counterion, which is an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid,

[0060] and the hydrate or solvate thereof.

[0061] The disclosure also relates to a pharmaceutical composition containing the radioisotope-labelled compound of quaternary ammonium salt of a polycyclic aromatic amine according to the disclosure and a pharmaceutically acceptable carrier or diluent, in particular to a pharmaceutical composition in the form of a sterile solution. The sterile composition is provided in the final container (vial or syringe) placed in an external shielding.

[0062] Compounds according to the disclosure are manufactured by adapting general synthetic methods available in the field of organic chemistry. The method illustrated in scheme I uses a substituted compound with formula II, wherein R.sup.1, R.sup.3 and R.sup.4 have the meanings indicated above for formula I, and wherein said compound with formula II is a derivative of acridine or phenanthridine, and it uses a compound GO.sup.A—CH.sub.2—R.sup.5(GO.sup.B) with formula III, wherein the GO.sup.A and GO.sup.B symbols are leaving groups substitutable with a nucleophilic reagent in a nucleophilic substitution reaction. The R.sup.5—CH.sub.2 fragment corresponds in terms of structure to the chain R.sup.2 substituent defined above. The GO.sup.A and GO.sup.B leaving groups are structurally identical or different and are independently selected from alkylsulfonate leaving groups, fluoroalkylsulfonate leaving groups, arylsulfonate leaving groups, haloarylsulfonate leaving groups and halogen leaving groups with the exclusion of fluoride group. Preferably, leaving groups are methanesulfonate, ethanesulfonate, trifluoromethanesulfonate (triflate), pentafluoroethanesulfonate, toluenesulfonate (tosyl), 4-bromophenylsulfonate (brosyl), iodide and bromide groups.

##STR00005##

[0063] In the first step of the synthesis, the substitution of the GO.sup.A group results in the formation of the acridinium or phenanthridinium compound with formula IV with the GO.sup.B leaving group in the side chain, and in the second step of the synthesis, the compound with formula IV is reacted with the .sup.18F.sup.− fluoride anion to form the compound with formula V containing the .sup.18F atom in the side chain attached to the quaternary nitrogen atom.

[0064] If required, R.sup.1 groups in a compound with formula II, which could be engaged in side reactions with a compound with formula III, are routinely protected using known protective groups, for example those disclosed in the monograph “Protective Groups in Organic Synthesis” (Theodora W. Greene and Peter G. M. Wuts, 2nd edition, 1991, John Wiley & Sons, Inc.). The R.sup.1 groups in the compound with formula II, that could be engaged in side reactions with the compound with formula III, are in particular primary and secondary amino groups, and optionally hydroxy groups.

[0065] Alternatively, the compounds according to the disclosure are manufactured by the method illustrated in scheme II using a substituted compound with formula II in which R.sup.1, R.sup.3 and R.sup.4 are as defined above for formula I, and the GO.sup.C—CH.sub.2—R.sup.6 compound with formula VI, wherein R.sup.6 is a .sup.18F fluorine atom or the CH.sub.2—R.sup.6 fragment corresponds to the definition of R.sup.2 in formula I, and the GO.sup.C symbol is a leaving group substitutable by a nitrogen atom of the acridine or phenanthridine ring in a nucleophilic substitution reaction. The GO.sup.C leaving group is selected from the leaving groups referred to above in the definition of the GO.sup.A and GO.sup.B groups. According to the method of scheme II, a compound with formula VII containing the .sup.18F atom in the side chain is manufactured, wherein the R.sup.6 fragment is the .sup.18F fluorine atom or the CH.sub.2—R.sup.6 fragment corresponds to the definition of R.sup.2 in formula I. Similarly to the reactions according to scheme I, if required, R.sup.1 groups in the compound with formula II, that could be engaged in side reactions with the compound with formula VI, are protected following the standard procedure using the protection groups as above.

##STR00006##

[0066] The compound according to the disclosure is obtained in the form of a quaternary ammonium salt together with a counterion, which is a mononegative anion of a stable organic or inorganic acid, corresponding to the leaving group departing in the last reaction step, in accordance with scheme I or II. The scope of the disclosure, however, is not limited to such salts, since the mononegative anion being the counterion in the quaternary salt can be replaced with another anion of a stable organic or inorganic acid as required using standard procedures. For example, the quaternary ammonium salt obtained by the method according to scheme I or II is dissolved in a solution of inorganic or organic salt containing the desired mononegative anion, or inorganic or organic salt containing the desired mononegative anion is added to the solution of the quaternary ammonium salt obtained by the method according to scheme I or II. Optionally, the quaternary ammonium salt obtained by the method according to scheme I or II shall be transformed into a salt containing the desired anion using ion exchangers, for example using the method disclosed in the paper entitled “An unusual substitution reaction directed by an intramolecular re-arrangement” (A. D. C. Parenty, L. V. Smith, L. Cronin), Tetrahedron, 61 (2005), pp. 8410-8418, using anion-exchange resin pre-treated with a solution of an alkali metal salt and acid of the desired anion, or recovered by way of elution with an appropriate buffer, in accordance with the procedure presented in the examples below.

[0067] Thus, the scope of subject disclosure covers a radioisotope-labelled compound of quaternary ammonium salt of a polycyclic aromatic amine with formula I, in which formula X.sup.− is a mononegative anion of any stable organic or inorganic acid, preferably an anion selected from the group comprising an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid.

[0068] Said salts can form hydrates and/or solvates, which hydrates and/or solvates are also included in the scope of the disclosure.

[0069] Preferably, the disclosure relates to a radioisotope-labelled compound with formula I, in which formula I the wavy line indicates a single bond between the non-nodal carbon atom of a polycyclic aromatic system and the R.sup.1 substituent,

[0070] R.sup.1 is a substituent independently selected from hydrogen, halogens, C.sub.1-4 alkoxy, a nitro group, an amino group optionally having 1 or 2 hydrogen atoms replaced with C.sub.1-4 alkyl, a chain C.sub.1-6 carbon group optionally having a halogen or C.sub.1-4 alkanesulfonic substituent, and a phenyl group optionally having 1-3 substituents independently selected from halogens, a chain C.sub.1-4 carbon substituent, a halogenated chain C.sub.1-4 carbon substituent, an amino group optionally having 1-2 atoms of hydrogen replaced with C.sub.1-4 alkyl,

[0071] R.sup.2 is a chain aliphatic substituent having the —CH.sub.2— fragment as the terminal member of the chain, to which chain a phenyl group is optionally attached optionally having 1-3 substituents selected from halogens and C.sub.1-6 alkyl, and, if the chain contains at least 2 carbon atoms, in which chain there is optionally a bivalent link between the carbon atoms of the chain, said link selected from the oxygen atom —O— and sulfur atom —S—, wherein the R.sup.2 substituent contains a total of 1-16 carbon atoms, and the hydrogen atom at one of the carbon atoms is replaced with an atom of .sup.18F fluorine radioisotope,

[0072] R.sup.3 and R.sup.4 are combined to form a butadienyl-1,3 substituent whose terminal carbon atoms are linked to the adjacent non-nodal carbon atoms of the B ring to form an aromatic C ring fused with the A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms,

[0073] n is an integer of 9,

[0074] X.sup.− is a pharmaceutically acceptable counterion, which is an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid,

[0075] and the hydrate or solvate thereof.

[0076] More preferably, the disclosure relates to a radioisotope-labelled compound with formula I, in which formula I the wavy line indicates a single bond between the non-nodal carbon atom of a polycyclic aromatic system and the R.sup.1 substituent,

[0077] R.sup.1 is a substituent independently selected from hydrogen, halogens, C.sub.1-4 alkoxy, an amino group optionally having 1-2 hydrogen atoms replaced with C.sub.1-4 alkyl, a chain C.sub.1-4 carbon group optionally having a halogen substituent, and a phenyl group optionally having 1-3 substituents independently selected from halogens, a chain C.sub.1-4 carbon substituent, a halogenated chain C.sub.1-4 carbon substituent, C.sub.1-4 alkoxy,

[0078] R.sup.2 is a chain aliphatic substituent having the —CH.sub.2— fragment as the terminal member of the chain, to which chain a phenyl group is optionally attached, optionally having 1-3 substituents selected from halogens and C.sub.1-6 alkyl, and, if the chain contains at least 2 carbon atoms, in which chain there is optionally a bivalent link between carbon atoms of the chain, said link being the oxygen atom —O—, wherein the R.sup.2 substituent contains a total of 1-16 carbon atoms, and the hydrogen atom at one of the carbon atoms is replaced with an atom of .sup.18F fluorine radioisotope,

[0079] R.sup.3 and R.sup.4 are combined to form a butadienyl-1,3 substituent whose terminal carbon atoms are linked to the adjacent non-nodal carbon atoms of the B ring to form an aromatic C ring fused with the A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms,

[0080] n is an integer of 9,

[0081] X.sup.− is a pharmaceutically acceptable counterion, which is an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid, and the hydrate or solvate thereof.

[0082] Even more preferably, the compound of the disclosure is a radioisotope-labelled compound with formula I, in which formula I the wavy line indicates a single bond between the non-nodal carbon atom of a polycyclic aromatic system and the R.sup.1 substituent,

[0083] R.sup.1 is a substituent independently selected from hydrogen, halogens, C.sub.1-4 alkoxy, an amino group optionally having 1-2 hydrogen atoms replaced with C.sub.1-2 alkyl, a chain C.sub.1-4 carbon group optionally having a halogen substituent, and a phenyl group optionally having 1-3 substituents independently selected from halogens, a chain C.sub.1-4 carbon substituent and a halogenated chain C.sub.1-4 carbon substituent,

[0084] R.sup.2 is a chain aliphatic substituent having the —CH.sub.2— fragment as the terminal member of the chain, to which chain a phenyl group is optionally attached optionally having 1-3 substituents selected from halogens and C.sub.1-4 alkyl, wherein the R.sup.2 substituent contains a total of 1-16 carbon atoms, and the hydrogen atom at one of the carbon atoms is replaced with an atom of .sup.18F fluorine radioisotope,

[0085] R.sup.3 and R.sup.4 are combined to form a butadienyl-1,3 substituent whose terminal carbon atoms are linked to the adjacent non-nodal carbon atoms of the B ring to form an aromatic C ring fused with the A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms,

[0086] n is an integer of 9,

[0087] X.sup.− is a pharmaceutically acceptable counterion, which is an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid, and the hydrate or solvate thereof.

[0088] Particularly preferably, the compound of the disclosure is a radioisotope-labelled compound with formula I, in which formula I the wavy line indicates a single bond between the non-nodal carbon atom of a polycyclic aromatic system and the R.sup.1 substituent,

[0089] R.sup.1 is a substituent independently selected from hydrogen, halogens, an amino group optionally having 1-2 hydrogen atoms replaced with C.sub.1-2 alkyl, a chain C.sub.1-4 carbon group, and a phenyl group optionally having 1-3 substituents independently selected from a chain C.sub.1-4 carbon substituent, a halogenated chain C.sub.1-4 carbon substituent,

[0090] R.sup.2 is a chain aliphatic substituent having the —CH.sub.2— fragment as the terminal member of the chain, to which chain a phenyl group is optionally attached optionally having a halogen substituent, wherein the R.sup.2 substituent contains a total of 1-16 carbon atoms, and the hydrogen atom at one of the carbon atoms is replaced with an atom of .sup.18F fluorine radioisotope,

[0091] R.sup.3 and R.sup.4 are combined to form a butadienyl-1,3 substituent whose terminal carbon atoms are linked to the adjacent non-nodal carbon atoms of the B ring to form an aromatic C ring fused with the A and B ring system, having R.sup.1 substituents at non-nodal carbon atoms,

[0092] n is an integer of 9,

[0093] X.sup.− is a pharmaceutically acceptable counterion, which is an anion of a mono-basic inorganic acid, a mononegative anion of a multi-basic inorganic acid, an anion of an alkane carboxylic acid, an anion of an aliphatic sulfonic acid, an anion of an aromatic sulfonic acid, an anion of an acidic amino acid,

[0094] and the hydrate or solvate thereof.

[0095] The following examples, which include: (i) examples of the manufacturing of intermediates in the manufacturing method of radioisotope-labelled compounds according to the disclosure, (ii) examples of the manufacturing of standard compounds for radioisotope-labelled compounds according to the disclosure and (iii) examples of the manufacturing of radioisotope-labelled compounds according to the disclosure, and (iv) examples of the formulation of a pharmaceutical composition, and (v) examples of the use of said compounds in diagnostic techniques, illustrate in detail the solution according to the disclosure without limiting the scope thereof. Throughout the examples, DCM stands for dichloromethane and ACN for acetonitrile.

[0096] The NMR spectra as quoted, were recorded using the ‘zg30’ sequence for proton and fluorine spectra and the ‘zg_pi_CPD (Bruker 500 MHz) or ‘s2pu1’ (Varian 300 MHz) sequence for carbon spectra, with hydrogen's proton decoupling. Proton spectra were calibrated against the TMS present in the sample (samples in chloroform) and against the residual signal of the DMSO solvent of 2.5 ppm (quintet). The external standard CFCl.sub.3 was used for the fluorine spectra measurement.

Example 1. 2-Fluoroethyl Trifluoromethanesulfonate

[0097] Trifluoromethanesulfonic acid anhydride (5.000 g; 17.72 mmol) is added to a 100 ml round-bottom single-neck flask with a magnetic dipole and septum. The flask is cooled to a temperature of 0° C. using a cooling bath (crushed ice+NaCl aqueous solution). DCM is added using a needle and syringe. A solution of 2-fluoroethanol (1.050 g; 16.39 mmol) and pyridine (1.570 g; 19.85 mmol) in 6 ml DCM is added dropwise over 20 minutes, and the whole is stirred for 2 h at room temperature. At the end of the reaction, the mixture is poured into 20 ml of cold water for HPLC. The post-reaction mixture is transferred to a separation funnel and washed three times with water. The organic phase is dried over MgSO.sub.4, and the solvent is then distilled off to dryness on a rotary evaporator to obtain 1.170 g of a pink liquid. Yield 36.4%

[0098] .sup.1H NMR (CDCl.sub.3, 500 MHz): δ 4.64-4.75 (m, 4H).

[0099] .sup.13C NMR (CDCl.sub.3, 125 MHz): δ 74.7 (d, .sup.2J.sub.C-F=20.25 Hz), 79.9 (d, .sup.1J.sub.C-F=173.88 Hz), 118.6 (q, .sup.1J.sub.C-F=317.13).

[0100] .sup.19F NMR (CDCl.sub.3, 470 MHz): −75.4 (s, 3F), −226.1-(−226.5) (m, 1F).

[0101] HR-MS C.sub.3H.sub.4F.sub.4O.sub.3S (196.12067 u).

Example 2. 1,2-Bis(trifluoromethanesulfonyloxy)ethane

[0102] Trifluoromethanesulfonic acid anhydride (5.000 g; 17.72 mmol) is added to a 100 ml round-bottom single-neck flask with a magnetic dipole and septum. The reaction flask is cooled to a temperature of 0° C. using a cooling bath (crushed ice+NaCl aqueous solution). 12 ml DCM is added using a needle and syringe, after which a solution of ethane-1,2-diol (0.540 g; 8.70 mmol) and pyridine (1.400 g; 17.70 mmol) in 6 ml DCM is added dropwise over 20 minutes, and the whole is stirred for 1.5 h at room temperature. At the end of the reaction, the mixture is poured into 20 ml of cold water for HPLC. The post-reaction mixture is transferred to a separation funnel and washed three times with water. The organic phase is dried over MgSO.sub.4, and the solvent is then distilled off to dryness on a rotary evaporator to obtain 2.200 g of a pink liquid. Yield 77.5%.

[0103] .sup.1H NMR (CDCl.sub.3, 500 MHz): δ 4.77 (s, 4H).

[0104] .sup.13C NMR (CDCl.sub.3, 125 MHz): δ 71.87, 118.5 (q, .sup.1J.sub.C-F=317.38 Hz).

[0105] .sup.19F NMR (CDCl.sub.3, 470 MHz): −74.7 (s, 6F).

Example 3. 1,6-Bis(trifluoromethanesulfonyloxy)hexane

[0106] Trifluoromethanesulfonic acid anhydride (7.000 g; 24.81 mmol) is added to a 100 ml round-bottom single-neck flask with a magnetic dipole and septum. The reaction flask is cooled to a temperature of 0° C. using a cooling bath (crushed ice+NaCl aqueous solution). 12 ml DCM is added using a needle and syringe, after which a solution of hexane-1,6-diol (1.400 g; 11.85 mmol) and pyridine (1.450 g; 18.33 mmol) in 50 ml DCM is added dropwise over 20 minutes. The whole is stirred for 3 h at room temperature. At the end of the reaction, the mixture is poured into 20 ml of cold water for HPLC. The post-reaction mixture is transferred to a separation funnel and washed three times with water. The organic phase is dried over MgSO.sub.4, and the solvent is then distilled off to dryness on a rotary evaporator to obtain 2.000 g of the product. Yield 44.2%.

[0107] .sup.1H NMR (CDCl.sub.3, 500 MHz): δ 1.51 (quint, 4H, .sup.3J.sub.H-H=4 Hz), 1.80-1.90 (m, 4H), 4.55 (t, .sup.3J.sub.H-H=6.5 Hz, 4H).

[0108] .sup.13C NMR (CDCl.sub.3, 125 MHz): δ 24.5, 28.9, 77.2, 118.6 (q, .sup.1J.sub.C-F=317.25 Hz).

[0109] .sup.19F NMR (CDCl.sub.3, 282 MHz): −75.0.

[0110] HR-MS C.sub.81H.sub.12F.sub.6O.sub.6S.sub.2 (382.29770 u).

Example 4. 1,3-Bis(trifluoromethane sulfonyloxy)propane

[0111] Trifluoromethanesulfonic acid anhydride (2.104 g; 7.46 mmol) is added to a 100 ml round-bottom single-neck flask with a magnetic dipole and septum. The reaction flask is cooled to a temperature of 0° C. using a cooling bath (crushed ice+NaCl aqueous solution). 12 ml DCM is added using a needle and syringe, after which a solution of propane-1,3-diol (0.261 g; 3.43 mmol) and pyridine (0.620 g; 7.84 mmol) in 6 ml DCM is added dropwise over 20 minutes, and the whole is stirred for 1.5 h at room temperature. At the end of the reaction, the mixture is poured into 20 ml of cold water for HPLC, transferred to a separation funnel and washed three times with water. The organic phase is dried over MgSO.sub.4, and the solvent is then distilled off to dryness on a rotary evaporator to obtain 0.938 g of the title compound in the form of a pink liquid. Yield 80.38%.

[0112] .sup.1H NMR (CDCl.sub.3, 500 MHz): δ 2.37 (q, .sup.3J.sub.H-H=5.5 Hz, 2H), 4.68 (t, .sup.3J.sub.H-H=6.0 Hz, 4H).

[0113] .sup.13C NMR (CDCl.sub.3, 125 MHz): δ 29.3, 71.5, 118.6 (q, .sup.1J.sub.C-F=319.60 Hz).

[0114] .sup.19F NMR (CDCl.sub.3, 470 MHz): −74.6 (s, 6F).

Example 5. 1,16-Bis(trifluoromethanesulfonyloxy)hexadecane

[0115] Trifluoromethanesulfonic acid anhydride (2.50 g; 8.86 mmol) and hexadecane-1,16-diol (0.252 g; 0.98 mmol) are added to a 100 ml round-bottom single-neck flask with a magnetic dipole and septum. The reaction is carried out at room temperature for 4 h. At the end of the reaction, the mixture is poured into 20 ml DCM and cold water for HPLC. The post-reaction mixture is transferred to a separation funnel and washed three times with water. The phase is dried over MgSO.sub.4, and the solvent is then distilled off to dryness on a rotary evaporator to obtain 0.301 g of the product. Yield 17.4%.

[0116] .sup.1H NMR (CDCl.sub.3, 500 MHz): δ 1.20-1.30 m (20H), 1.41 (quint, 4H, .sup.3J.sub.H-H=4 Hz), 1.82 (quint, .sup.3J.sub.H-H=4 Hz, 4H), 4.54 (t, .sup.3J.sub.H-H=6.5 Hz, 4H).

[0117] .sup.13C NMR (CDCl.sub.3, 125 MHz): δ 25.0, 28.8, 29.2, 29.3, 29.4, 29.6, 29.6, 77.8, 118.6 (q, .sup.1J.sub.C-F=317.25 Hz).

[0118] .sup.19F NMR (CDCl.sub.3, 470 MHz): −74.9.

Example 6. 2-(4-Fluorophenyl)ethyl trifluoromethanesulfonate

[0119] Trifluoromethanesulfonic acid anhydride (2.000 g; 7.09 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole and septum. The solution is cooled to a temperature of 0° C. using a cooling bath (ice+NaCl), 2-(4-fluorophenyl)ethanol (0.921 g; 6.57 mmol) is added dropwise to the cooled solution over about 10 minutes, and the contents of the flask are stirred for 4 h at room temperature. At the end of the reaction, the mixture is poured into 20 ml DCM and cold water for HPLC. The reaction mixture is transferred to a separation funnel and washed repeatedly with water to remove the acid. The phase is dried over MgSO.sub.4, and the solvent is then distilled off on a rotary evaporator to obtain 0.999 g of the product. Yield 55.8%.

[0120] .sup.1H NMR (CDCl.sub.3, 500 MHz): δ 3.10 (t, .sup.3J.sub.H-H=7.0 Hz), 4.66 (td, .sup.3J.sub.H-H=7.0 Hz, .sup.4J.sub.H-F=0.5 Hz, 2H), 7.03 (dd, .sup.3J.sub.H-F=9.0 Hz, .sup.4J.sub.H-H=5.0 Hz, 2H), 7.16-7.20 (m, .sup.3J.sub.H-H=7.0 Hz, 2H).

[0121] .sup.13C NMR (CDCl.sub.3, 125 MHz): δ 35.24, 77.55, 116.2 (d, .sup.2J.sub.C-F=21.5 Hz), 118.6 (q, .sup.1J.sub.C-F=317.13), 130.8090 (d, .sup.3J.sub.C-F=8.0 Hz), 130.8095 (d, .sup.4J.sub.C-F=3.4 Hz), 162.5 (d, .sup.1J.sub.C-F=246.2 Hz).

[0122] .sup.19F NMR (CDCl.sub.3, 282 MHz): −74.8 (s, 3F), −115.0 (tt, .sup.3J.sub.F-H=8.8 Hz, .sup.4J.sub.F-H=5.0 Hz, 1F).

Example 7. 5-(2-Fluoroethyl)phenanthridinium p-toluenesulfonate

[0123] Phenanthridine (0.410 g; 2.29 mmol) is added to a 100 ml round-bottom single-neck flask in an inert gas atmosphere, after which 1 ml of toluene is added three times using a needle and syringe, which is then distilled off to dryness. Phenanthridine dissolved in DMF is added dropwise to 2-fluoroethyl tosylate (1.000 g; 4.58 mmol) in DMF, contained in a 100 ml round-bottom single-neck flask equipped with a magnetic dipole and mounted on a magnetic stirrer. The reaction is carried out in an inert gas atmosphere for 168 h at 105° C. At the end of the reaction, the yellow to brown solution is concentrated on a rotary evaporator to remove DMF. The residue is cooled to room temperature and dissolved in cold acetone (about 4 ml). Diethyl ether (about 60 ml) is added, and this is cooled in a refrigerator. The precipitated product is filtered off. 0.20 g of the title compound is obtained (22.0% yield).

[0124] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 5.09 (td, .sup.2J.sub.H-F=47 Hz, .sup.3J.sub.H-H=4.5 Hz, 2H), 5.53 (td, .sup.3J.sub.H-F=26 Hz, .sup.3J.sub.H-H=4.5 Hz, 2H), 7.94-8.04 (m, 4H), 8.10-8.17 (m, 4H), 8.20-8.30 (m, 4H), 8.41-8.45 (m, 1H), 8.54 (dd, .sup.3J.sub.H-H=8 Hz, .sup.4J.sub.H-H=0.5 Hz, 1H), 8.62-8.69 (m, 2H), 9.00-9.06 (m, 2H), 9.16 (d, .sup.3J.sub.H-H=8 Hz, 1H), 9.21 (dd, .sup.3J.sub.H-H=8 Hz, .sup.4J.sub.H-H2 Hz), 10.37 (s, 1H).

[0125] .sup.19F NMR ((CD.sub.3).sub.2SO, 470 MHz): δ −221.1 (tt, .sup.2J.sub.F-H=47.1 Hz, .sup.3J.sub.H-H=25.9 Hz, 1F).

[0126] HR-MS C.sub.7H.sub.7S.sub.1O.sub.3.sup.− (171.01104 u), found: 171.01122 u, C.sub.15H.sub.13N.sub.1F.sub.1.sup.+ (226.10265 u), found: 226.10250 u.

Example 8. 6-Phenyl-5-(2-fluoroethyl)phenanthridinium trifluoromethanesulfonate

[0127] 2-Fluoroethyl trifluoromethanesulfonate (0.290 g; 1.48 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 6 ml DCM is added using a needle and syringe. The solution is cooled to a temperature of −56° C. using a cooling bath (liquid nitrogen+ethyl acetate). A solution of 6-phenylphenanthridine (0.210 g; 0.82 mmol) in 6 ml DCM is added dropwise to the cooled solution over about 20 minutes. The contents of the flask are stirred for 216 h. At the end of the reaction, cold Et.sub.2O is added to the reaction mixture. The mixture is left in the refrigerator for 30 min, after which the product is filtered under reduced pressure. 0.200 g of the title compound is obtained (53.9% yield).

[0128] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 4.95 (dt, .sup.2J.sub.H-F=46.5 Hz, .sup.3J.sub.H-H=5.0 Hz, 2H), 5.30 (dbs, .sup.3J.sub.H-F=23.5 Hz, 2H), 7.56 (d, .sup.3J.sub.H-H=8 Hz, 1H), 7.75-7.88 (m, 5H), 7.96 (t, .sup.3J.sub.H-H=7.5 Hz, 1H), 8.15-8.23 (m, 2H), 8.48 (ddd, .sup.3J.sub.H-H=8.5 Hz, .sup.3J.sub.H-H=7.0 Hz, .sup.4J.sub.H-H=1.5 Hz, 1H), 8.75 (d, .sup.3J.sub.H-H=9 Hz, 1H), 9.28 (d, .sup.3J.sub.H-H=8 Hz, 1H), 9.32 (dd, .sup.3J.sub.H-H=8.5 Hz, .sup.4J.sub.H-H=1.5 Hz, 1H).

[0129] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz): δ 54.1 (d, .sup.2J.sub.C-F=21.00 Hz), 81.3 (d, .sup.1J.sub.C-F=170.00 Hz), 121.1, 123.3, 124.8, 125.5, 126.0, 128.9, 129.2, 130.4, 130.6, 130.9, 131.4, 132.3, 132.9, 134.2, 134.7, 137.8, 165.3.

[0130] .sup.19F NMR ((CD.sub.3).sub.2SO, 470 MHz): δ −78.1 (s, 3F), −220.4-−220.8 (tt, .sup.2J.sub.F-H=49.0 Hz, .sup.3J.sub.H-H=22.1 Hz, 1F).

[0131] HR-MS C.sub.1O.sub.3F.sub.3S.sub.1.sup.− (148.95148 u), found: 148.95106 u, C.sub.21H.sub.17FN.sup.+ (302.36423 u).

Example 9. 10-(2-Fluoroethyl)acridinium trifluoromethanesulfonate

[0132] 2-Fluoroethyl trifluoromethanesulfonate (0.270 g; 1.38 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 6 ml DCM is added using a needle and syringe. The solution is cooled to a temperature of −56° C. using a cooling bath (liquid nitrogen+ethyl acetate). A solution of acridine (0.220 g; 1.23 mmol) in 6 ml DCM is added dropwise to the cooled solution over about 20 minutes, after which the contents of the flask are stirred for 72 h. At the end of the reaction, 20 ml of cold Et.sub.2O is added to the reaction mixture, the mixture is left in the refrigerator for 30 min, and then the product is filtered off under reduced pressure. 0.200 g of the title compound is obtained. Yield 43.4%.

[0133] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 5.15 (dt, .sup.2J.sub.H-F=47 Hz, .sup.3J.sub.H-H=4.5 Hz, 2H), 5.91 (dt, .sup.3J.sub.H-F=25.5 Hz, J=4.5 Hz, 2H), 8.06 (dd, .sup.3J.sub.H-H=8.5 Hz, .sup.3J.sub.H-H=7.0 Hz, 2H), 8.48 (ddd, .sup.3J.sub.H-H=9.5 Hz, .sup.3J.sub.H-H=7.0 Hz, .sup.4J.sub.H-H=1.5 Hz, 2H), 8.67 (dd, .sup.3J.sub.H-H=8 Hz, .sup.4J.sub.H-H=1.5 Hz, 2H), 8.80 (d, .sup.3J.sub.H-H=9.5 Hz, 2H), 10.26 (s, 1H).

[0134] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz): δ 49.9 (d, .sup.2J.sub.C-F=19.12 Hz), 82.3 (d, .sup.1J.sub.C-F=168.88 Hz), 118.9, 126.4, 127.8, 132.0, 139.4, 141.5, 152.1.

[0135] .sup.19F NMR ((CD.sub.3).sub.2SO, 470 MHz): δ −78.1 (s, 3F), −221.5 (tt, .sup.2J.sub.F-H=47 Hz, .sup.2J.sub.F-H=25.5 Hz, 1F).

[0136] HR-MS C.sub.1O.sub.3F.sub.3S.sub.1.sup.− (148.95148 u), C.sub.15H.sub.13N.sub.1F.sub.1.sup.+ (226.10265 u), found: 226.10250 u.

Example 10. 3,6-Bis(dimethylamino)-10-(2-fluoroethyl)acridinium trifluoromethanesulfonate

[0137] 2-Fluoroethyl trifluoromethanesulfonate (0.218 g; 1.11 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 10 ml DCM is added using a needle and syringe. The solution is cooled to a temperature of −56° C. using a cooling bath (liquid nitrogen+ethyl acetate). A solution of Acridinium Orange (0.137 g; 0.52 mmol) in 10 ml DCM is added dropwise to the cooled solution over about 20 minutes, after which the contents of the flask are stirred for 72 h. At the end of the reaction, 20 ml of cold Et.sub.2O is added to the reaction mixture, the mixture is left in the refrigerator for 30 min, and then the product is filtered off under reduced pressure. 0.104 g of the title compound is obtained (57.5% yield).

[0138] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 3.19 (s, 12H), 4.90-5.10 (m, 4H), 6.54 (s, 2H), 7.10 (d, .sup.3J.sub.H-H=9 Hz, 2H), 7.73 (d, .sup.3J.sub.H-H=9 Hz, 2H), 8.56 (s, 1H).

[0139] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz): δ 40.2, 46.8 (d, .sup.2J.sub.C-F=19.9 Hz), 81.6 (d, .sup.1J.sub.C-F=167.6 Hz), 92.9, 114.0, 116.2, 120.7 (q, .sup.1J.sub.C-F=320 Hz), 132.8, 142.6, 143.0, 155.2.

[0140] .sup.19F NMR ((CD.sub.3).sub.2SO, 282 MHz): δ −77.71 (s, 3F), −221.3 (tt, .sup.2J.sub.F-H=49.4 Hz, .sup.3J.sub.H-H=25.1 Hz, 1F).

[0141] HR-MS C.sub.3F.sub.3S.sub.1O.sub.3.sup.− (148.95148 u), found: 148.95106 u, C.sub.19H.sub.23FN.sub.3 (312.40387 u).

Example 11. 5-(2-Trifluoromethylsulfonyloxyethyl)phenanthridinium trifluoromethanesulfonate

[0142] 1,2-Bis(trifluoromethanesulfonyloxy)ethane (0.310 g, 0.95 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 6 ml DCM is added using a needle and syringe. The solution is cooled to a temperature of −56° C. using a cooling bath (liquid nitrogen+ethyl acetate). A solution of phenanthridine (0.170 g, 0.95 mmol) in 10 ml DCM is added dropwise to the cooled solution over about 20 minutes, after which the contents of the flask are stirred for 48 h. At the end of the reaction, 20 ml of cold Et.sub.2O is added to the reaction mixture, the mixture is left in the refrigerator for 30 min, and then the product is filtered off under reduced pressure. 0.160 g of the title compound is obtained (33.3% yield).

[0143] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 4.88 (t, .sup.3J.sub.H-H=4.5 Hz, 2H), 5.48 (t, .sup.3J.sub.H-H=4.5 Hz, 2H), 8.10-8.25 (m, 3H), 8.46 (ddd, .sup.3J.sub.H-H=8.0 Hz, .sup.3J.sub.H-H=7.0 Hz, .sup.4J.sub.H-H=1.0 Hz, 2H), 8.66 (dd, .sup.3J.sub.H-H=8.0 Hz, .sup.4J.sub.H-H=1.0 Hz, 2H), 9.19 (d, .sup.3J.sub.H-H=8.5 Hz, 1H), 9.24 (dd, .sup.3J.sub.H-H=8.5 Hz, .sup.4J.sub.H-H=2.0 Hz, 1H), 10.23 (s, 1H).

[0144] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz); δ 56.9, 73.1, 120.0, 120.7 (q, .sup.1J.sub.C-F=320.25), 123.2, 123.5, 125.1, 126.0, 130.4, 130.5, 132.0, 133.1, 133.6, 134.8, 138.6, 156.6.

[0145] .sup.19F NMR ((CD.sub.3).sub.2SO, 470 MHz); δ −78.1 (s, 3F).

[0146] HR-MS C.sub.1F.sub.3S.sub.1O.sub.3.sup.− (148.95148 u), found: 148.95147 u, C.sub.16H.sub.13N.sub.1S.sub.1O.sub.3F.sub.3.sup.+ (356.05628 u), found: 356.05616 u.

Example 12. 6-Phenyl-5-(2-trifluoromethylsulfonyloxyethyl)phenanthridinium trifluoromethanesulfonate

[0147] 1,2-Bis(trifluoromethanesulfonyloxy)ethane (0.404 g; 1.24 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 6 ml DCM is added using a needle and syringe. The solution is cooled to a temperature of −56° C. using a cooling bath (liquid nitrogen+ethyl acetate), 6-phenylphenanthridine solution (0.170 g; 0.67 mmol) in 6 ml DCM is added dropwise over about 20 minutes to the cooled solution, and the contents of the flask are then stirred for 96 h. At the end of the reaction, the mixture is concentrated to 8 ml, 40 ml of cold Et.sub.2O is added, and this is left in the refrigerator for 30 minutes. The product is filtered under reduced pressure to obtain 0.200 g of the title compound (51.7% yield).

[0148] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 4.70 (t, 2H, .sup.3J.sub.H-H=4.5 Hz), 5.26 (bs, 2H), 7.58 (d, 1H, .sup.3J.sub.H-H=8.5 Hz), 7.72-7.88 (m, 5H), 7.98 (t. 1H, J=7.5 Hz), 8.15-8.25 (m, 2H), 8.42 (t, 1H, J=8.0 Hz), 8.65 (d, 1H, .sup.3J.sub.H-H=9.5 Hz), 9.29 (d, 1H, .sup.3J.sub.H-H=8.5 Hz), 9.34 (d, 1H, .sup.3J.sub.H-H=9.5 Hz).

[0149] .sup.19F NMR ((CD.sub.3).sub.2SO, 470 MHz): δ −78.1 (s, 3F).

[0150] MS-HR C.sub.1O.sub.3F.sub.3S.sub.1.sup.− (148.95148), found: 148.95106, C.sub.22H.sub.17F.sub.3NO.sub.3S (432.43484 u) found: 432.08751 u.

Example 13. 10-(2-Trifluoromethylesulfonyloxyethyl)acridinium trifluoromethanesulfonate

[0151] 1,2-Bis(trifluoromethanesulfonyloxy)ethane (0.29 g, 0.89 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 6 ml DCM is added using a needle and syringe. The solution is cooled to a temperature of −56° C. using a cooling bath (liquid nitrogen+ethyl acetate), acridine solution (0.120 g; 0.67 mmol) in 6 ml DCM is added dropwise over about 20 minutes to the cooled solution, and the contents of the flask are then stirred for 48 h. At the end of the reaction, the mixture is concentrated to 4 ml, 20 ml of cold Et.sub.2O is added, and this is left in the refrigerator for 30 minutes. The product is filtered under reduced pressure to obtain 0.03 g of the title compound. Yield 8.86%.

[0152] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 5.39 (t, .sup.3J.sub.H-H=5.0 Hz, 2H), 6.02 (t, .sup.3J.sub.H-H=5.0 Hz, 2H), 8.00-8.10 (dd, .sup.3J.sub.H-H=8.0 Hz, .sup.3J.sub.H-H=7.0 Hz, 2H), 8.15 (ddd, .sup.3J.sub.H-H=9.0 Hz, .sup.3J.sub.H-H=7.0 Hz, .sup.4J.sub.H-H=1.5 Hz, 2H), 8.32 (d, .sup.3J.sub.H-H=9.5 Hz, 2H), 8.47 (dd, .sup.3J.sub.H-H=8.5 Hz, .sup.4J.sub.H-H=1 Hz, 2H), 9.99 (s, 1H).

[0153] .sup.19F FMR ((CD.sub.3).sub.2SO, 470 MHz): δ −78.1 (s, 3F).

[0154] MS-HR C.sub.3F.sub.3S.sub.1O.sub.3.sup.− (148.95148), found: 148.95106, C.sub.16H.sub.13F.sub.3NO.sub.3S.sup.+ (356.338981 u).

Example 14. 3,6-Bisdimethylamino-10-(2-trifluoromethylesulfonyloxyethyl)-acridinium trifluoromethanesulfonate

[0155] 1,2-Bis(trifluoromethanesulfonyloxy)ethane (0.355 g, 1.09 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 6 ml DCM is added using a needle and syringe. The solution is cooled to a temperature of −56° C. using a cooling bath (liquid nitrogen+ethyl acetate), and a solution of Acridinium Orange (0.207 g, 0.78 mmol) in 6 ml DCM is added dropwise to the cooled solution over about 20 minutes. The contents of the flask are stirred for 96 h and, at the end of the reaction, concentrated to 4 ml, and 20 ml of cold Et.sub.2O is added. The mixture is left in the refrigerator for 30 min, after which the product is filtered under reduced pressure to obtain 0.310 g of the title compound. Yield 67.2%.

[0156] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 3.27 (s, 12H), 4.85 (t, .sup.3J.sub.H-H=4.5 Hz, 2H), 5.15 (bs, 2H), 6.63 (s, 2H), 7.25 (d, .sup.3J.sub.H-H=9.0 Hz, 2H), 7.89 (d, .sup.3J.sub.H-H=7.5 Hz, 2H), 8.76 (s, 1H).

[0157] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz): δ 40.4, 57.8, 73.2, 93.1, 114.2, 116.4, 120.7 (q, .sup.1J.sub.C-F=320 Hz), 133.0, 143.0, 155.5.

[0158] .sup.19F NMR ((CD.sub.3).sub.2SO, 470 MHz): δ −78.1 (s, 3F).

Example 15. 5-(3-Fluoropropropyl)phenanthridinium trifluoromethanesulfonate

[0159] The title compound is obtained by following the procedure described in example 7, but using 3-fluoropropropyl trifluoromethanesulfonate (0.229 g, 1.09 mmol) instead of 2-fluoroethyl trifluoromethanesulfonate and phenanthridine (0.230 g, 1.28 mmol). Yield 71.0%.

[0160] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 2.46-2.58 (m, 2H), δ 4.73 (dt, .sup.2J.sub.H-F=47 Hz, .sup.3J.sub.H-H=5.5 Hz, 2H), 5.24 (t, .sup.3J.sub.H-H=7 Hz, 2H), 8.09-8.14 (m, 2H), 8.14-8.19 (m, 1H), 8.37-8.43 (m, 1H), 8.59 (dd, .sup.3J.sub.H-H=8 Hz, .sup.4J.sub.H-H=1 Hz, 1H), 8.63 (d, .sup.3J.sub.H-H=8 Hz, 1H), 9.12 (d, .sup.3J.sub.H-H=8 Hz, 1H), 9.18 (dd, .sup.3J.sub.H-H=8 Hz, .sup.4J.sub.H-H=1 Hz, 1H), 10.37 (s, 1H).

[0161] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz): δ 29.8 (d, .sup.1J.sub.C-F=19.375 Hz), δ 55.0 (d, .sup.1J.sub.C-F=4.5 Hz), 81.5 (d, .sup.1J.sub.C-F=161.0 Hz), 119.8, 120.7 (q, .sup.1J.sub.C-F=320.25 Hz), 123.1, 123.7, 125.1, 125.9, 130.3, 130.4, 132.1, 132.8, 133.1, 134.4, 138.1, 155.9.

[0162] .sup.19F NMR ((CD.sub.3).sub.2SO, 470 MHz): δ −219.7-−220.1 (m, 1F), −77.72 (s, 3F).

Example 16. 5-[2-(4-Fluorophenyl)ethyl]phenanthridinium trifluoromethanesulfonate

[0163] The title compound is obtained by following the procedure described in example 7, but using 2-(4-fluorophenyl)ethyl trifluoromethanesulfonate (0.174 g, 0.64 mmol) instead of 2-fluoroethyl trifluoromethanesulfonate and phenanthridine (0.147 g, 0.82 mmol). 0.198 g of the product is obtained (53.7% yield).

[0164] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 3.41 (.sup.3J.sub.H-H=7.5 Hz. 2H). 5.33 (t. .sup.3J.sub.H-H=7.5 Hz. 2H), 7.09-7.14 (m. 2H). 7.27-7.33 (m, 2H), 8.10 (ddd, .sup.3J.sub.H-H=8.0 Hz, .sup.3J.sub.H-H=7.5 Hz, .sup.4J.sub.H-H=1.0 Hz, 1H), 8.14 (ddd, .sup.3J.sub.H-H=8.0 Hz, .sup.3J.sub.H-H=7.5 Hz, .sup.4J.sub.H-H=1.5 Hz, 1H), 8.19 (ddd, .sup.3J.sub.H-H=9.0 Hz, .sup.3J.sub.H-H=7.5 Hz, .sup.4J.sub.H-H=1.5 Hz, 1H), 8.41 (ddd, .sup.3J.sub.H-H=8.5 Hz, .sup.3J.sub.H-H=7.0 Hz, .sup.4J.sub.H-H=1.5 Hz, 1H), 8.48 (dd, .sup.3J.sub.H-H=8.0 Hz, .sup.4J.sub.H-H=1.0 Hz, 1H), 8.74 (dd, .sup.3J.sub.H-H=8.5 Hz, .sup.4J.sub.H-H=1.0 Hz, 1H), 9.15 (d, .sup.3J.sub.H-H=8.5 Hz, 1H), 9.21 (dd, .sup.3J.sub.H-H=8 Hz, .sup.4J.sub.H-H=1.5 Hz, 1H), 10.13 (s, 1H).

[0165] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz): δ 34.1, 58.5, 115.4 (d, .sup.2J.sub.C-F=21.3 Hz), 120.1, 120.7 (q, .sup.1J.sub.C-F=320.25 Hz), 123.2, 123.4, 125.1, 125.8, 130.5, 130.4, 131.0 (d, .sup.3J.sub.C-F=8.2 Hz), 132.2, 132.6 (d, .sup.4J.sub.C-F=3.1 Hz), 132.2 132.7, 132.9, 134.4, 138.2, 155.5, 161.3 (d, .sup.1J.sub.C-F=243.2 Hz).

[0166] .sup.19F NMR ((CD.sub.3).sub.2SO, 470 MHz): δ −77.72 (s, 3F), −115.6-−115.5 (m, 1F).

Example 17. 10-(2-Iodoethyl)acridinium iodide

[0167] 1.2-Diiodoethane (1.033 g, 3.66 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. Acridine (0.406 g, 2.26 mmol) dissolved in 10 ml toluene is added using a needle and syringe, and the reaction is carried out at solvent boiling point for 10 h. The mixture is cooled, the precipitate formed is filtered off and washed with diethyl ether. 0.433 g of a compound with 33% purity (according to HPLC) is obtained.

[0168] 1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 3.79 (t, .sup.3J.sub.H-H=7.5 Hz, 2H), 5.76 (t, .sup.3J.sub.H-H=7.5 Hz, 2H), 8.03 (dd, .sup.3J.sub.H-H=8.0 Hz, .sup.3J.sub.H-H=7.0 Hz, 2H), 8.48 (ddd, .sup.3J.sub.H-H=8.5 Hz, .sup.3J.sub.H-H=7.5 Hz, .sup.4J.sub.H-H=1.5 Hz, 2H), 8.63 (dd, .sup.3J.sub.H-H=8.5 Hz, .sup.4J.sub.H-H=1.5 Hz, 2H), 8.69 (d, .sup.3J.sub.H-H=9.5 Hz, 2H) 10.20 (s, 1H).

Example 18. 5-(16-Trifluoromethylsulfonyloxyhexadecyl)phenanthridinium trifluoromethanesulfonate

[0169] 1,16-Bis(trifluoromethanesulfonyloxy)hexadecane (0.145 g, 0.28 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 15 ml DCM is added using a needle and syringe. A solution of phenanthridinium (0.033 g, 0.18 mmol) in 15 ml DCM is added dropwise to the solution over about 20 minutes, after which the contents of the flask are stirred for 96 h. At the end of the reaction, DCM is evaporated, and the residue is washed with diethyl ether. 0.038 g of the title compound is obtained. Yield 19.5%.

[0170] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 1.1-1.4 (m, 20H), 1.45 (bs, 2H), 2.06 (bs, 2H), 4.5-4.7 (bs, 2H), 5.08 (t, 2H, .sup.3J.sub.H-H=7.5 Hz), 8.07-8.17 (m, 3H), 8.40 (ddd .sup.3J.sub.H-H=8.5 Hz, .sup.3J.sub.H-H=7.5 Hz, .sup.3J.sub.H-H=1.5 Hz, 1H), 8.58 (d, .sup.3J.sub.H-H=8.0 Hz, 1H), 8.64 (d, .sup.3J.sub.H-H=8.5 Hz, 1H), 9.14 (d, .sup.3J.sub.H-H=8.0 Hz, 1H), 9.19 (dd, .sup.3J.sub.H-H=8.0 Hz, .sup.4J.sub.H-H=1.5 Hz, 1H), 10.32 (s, 1H).

[0171] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz): δ 24.7, 25.5, 25.7, 25.9, 28.5, 28.6, 28.8, 28.86, 28.91, 28.96, 29.00, 29.02, 29.06, 29.09, 60.7, 76.2, 119.4, 120.7 (q, .sup.1J.sub.C-F=320.25), 123.2, 123.7, 125.0, 125.9, 130.3, 130.4, 132.1, 132.8, 133.1, 134.4, 138.0, 155.3.

Example 19. 6-[4-(Chloromethyl)phenyl]-5-(2-fluoroethyl)phenanthridinium trifluoromethanesulfonate

[0172] 2-Fluoroethyl trifluoromethanesulfonate (0.091 g, 0.46 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 6 ml DCM is added using a needle and syringe. A solution of 6-[4-(chloromethyl)phenyl]phenanthridine (0.071 g, 0.23 mmol) in 6 ml DCM is added dropwise to the cooled solution over about 20 minutes. The contents of the flask are mixed for 70.5 h. At the end of the reaction, cold Et.sub.2O (40 ml) is added to the reaction mixture. The mixture is left in the refrigerator for 30 min, after which the product is filtered under reduced pressure. 0.019 g of the title compound is obtained (15.6% yield).

[0173] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 4.93 (dt, .sup.2J.sub.H-F=47.0 Hz, .sup.3J.sub.H-H=4.5 Hz, 2H), 4.99 (s, 2H), 5.27 (bd, .sup.3J.sub.H-F=23.5 Hz), 7.54 (dd, .sup.3J.sub.H-H=8.5 Hz, .sup.4J.sub.H-H=1.0 Hz, 1H), 7.80 (d, .sup.3J.sub.H-H=8.0 Hz, 2H), 7.87 (d, .sup.3J.sub.H-H=8.0 Hz, 2H), 7.97 (ddd, .sup.3J.sub.H-H=8.5 Hz, .sup.3J.sub.H-H=7.0 Hz, .sup.4J.sub.H-H=1.0 Hz, 1H), 8.17-8.23 (m, 2H), 8.41 (ddd, .sup.3J.sub.H-H=8.0 Hz, .sup.3J.sub.H-H=7.0 Hz, .sup.4J.sub.H-H=1.5 Hz, 1H), 8.74 (d, .sup.3J.sub.H-H=9.5 Hz, 1H), 9.28 (d, .sup.3J.sub.H-H=8.5 Hz, 1H), 9.33 (dd, .sup.3J.sub.H-H=7.0 Hz, .sup.4J.sub.H-H=2.0 Hz, 1H).

[0174] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz): δ 45.3, 54.2 (d, .sup.2J.sub.C-F=21.3 Hz), 81.3 (d, .sup.2J.sub.C-F=170.7 Hz), 121.1, 120.7 (q, .sup.1J.sub.C-F=320.25 Hz), 120.8, 123.3, 124.9, 125.4 126.0, 129.4, 130.5, 130.6, 130.7, 132.3, 132.8, 134.1, 134.7, 137.8, 140.9, 164.9.

[0175] .sup.19F NMR ((CD.sub.3).sub.2SO, 282 MHz): δ −77.7 (s, 3F), −220.2 (tt, 46.9, 24.0, 1F).

[0176] HR-MS C.sub.1O.sub.3F.sub.3S.sub.1.sup.− (148.95148), found: 148.95106, C.sub.22H.sub.18FClN.sup.+ (350.11063), found: 350.11040.

Example 20. 9-Chloro-10-[2-(4-fluorophenyl)ethyl]acridinium trifluoromethanesulfonate

[0177] 2-(4-Fluorophenyl)ethyl trifluoromethanesulfonate (0.068 g, 0.25 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 6 ml DCM is added using a needle and syringe. A solution of 9-chloroacridine (0.057 g, 0.27 mmol) in 6 ml DCM is added dropwise to the solution over about 20 minutes. The contents of the flask are mixed for 19 h. At the end of the reaction, cold Et.sub.2O (40 ml) is added to the reaction mixture. The mixture is left in the refrigerator for 30 min, after which the product is filtered under reduced pressure. 0.001 g of the title compound is obtained (0.6% yield).

[0178] HR-MS C.sub.1O.sub.3F.sub.3S.sub.1.sup.− (148.95148), found: 148.95106, C.sub.21H.sub.16FClN.sup.+ (336.09498), found: 336.09481.

Example 21. 6-(4-Butylphenyl)-5-[2-(4-fluorophenyl)ethyl]phenanthridinium trifluoromethanesulfonate

[0179] The title compound is obtained by following the procedure described in example 20, but using 6-(4-butylphenyl)phenanthridine (0.103 g, 0.33 mmol) instead of 9-chloroacridine and 2-(4-fluorophenyl)ethyl trifluoromethanesulfonate (0.1955 g, 0.72 mmol). 0.032 g of the product is obtained (16.5% yield).

[0180] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 0.98 (t, .sup.3J.sub.H-H=7.5 Hz, 3H), 1.39 (sext, .sup.3J.sub.H-H=7.5 Hz, 2H), 1.71 (quint, .sup.3J.sub.H-H=7.5 Hz, 2H), 2.82 (t, .sup.3J.sub.H-H=7.5 Hz, 3H), 3.26 (t, .sup.3J.sub.H-H=7.5 Hz, 2H), 4.94 (bs, 2H), 6.97-7.10 (m, 4H), 7.60-7.75 (m, 5H), 7.97 (t, .sup.3J.sub.H-H=8.0 Hz, 1H), 8.20-8.30 (m, 2H), 8.40 (td, .sup.3J.sub.H-H=8.0 Hz, .sup.4J.sub.H-H=1.0 Hz, 1H), 8.90 (d, .sup.3J.sub.H-H=8.5 Hz, 1H), 9.26 (d, .sup.3J.sub.H-H=10.00 Hz, 1H), 9.33 (dd, .sup.3J.sub.H-H=8.5 Hz, .sup.4J.sub.H-H=1.0 Hz, 1H).

[0181] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz): δ 13.8, 21.6, 33.0, 33.5, 34.7, 55.3, 115.3 (d, .sup.2J.sub.C-F=21.3, 21.00 Hz), 121.0, 120.7 (q, .sup.1J.sub.C-F=320.25 Hz), 123.2, 124.9, 125.6 125.9, 128.4, 129.2, 133.0, 133.5, 130.5 (d, .sup.3J.sub.C-F=8.2 Hz), 132.5, 132.7, 132.7 (d, .sup.4J.sub.C-F=2.9 Hz), 133.8, 134.5, 137.5, 161.3 (d, .sup.1J.sub.C-F=243.5 Hz), 164.6.

[0182] .sup.19F NMR ((CD.sub.3).sub.2SO, 470 MHz); δ −77.7 (s, 3F), −115.5-−115.4 (m, 1F).

Example 22. 6-Phenyl-5-(3-fluoropropyl)phenanthridinium trifluoromethanesulfonate

[0183] 3-Fluoropropropyl trifluoromethanesulfonate (0.159 g, 0.76 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 6 ml DCM is added using a needle and syringe. The solution is cooled to a temperature of −56° C. using a cooling bath (liquid nitrogen+ethyl acetate). A solution of 6-phenylphenanthridine (0.149 g, 0.58 mmol) in 6 ml DCM is added dropwise to the cooled solution over about 20 minutes. The contents of the flask are mixed for 96 h. At the end of the reaction, the product is concentrated on an evaporator, cold Et.sub.2O is added, and the mixture is left in the refrigerator for 30 minutes. The precipitated product is filtered off under reduced pressure. 0.136 g of the title compound is obtained (50.0% yield).

[0184] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 2.36 (dq, .sup.3J.sub.H-F=27.0 Hz, .sup.3J.sub.H-H=5.5 Hz, 2H), 4.51 (dt, .sup.2J.sub.H-F=47.0 Hz, .sup.3J.sub.H-H=4.5 Hz, 2H), 5.27 (bs, 2H), 7.56 (dd, .sup.3J.sub.H-H=8.5 Hz, .sup.4J.sub.H-H=1.0 Hz, 1H), 7.80-7.85 (m, 5H), 7.95 (ddd, .sup.3J.sub.H-H=7.5 Hz, .sup.3J.sub.H-H=7.0 Hz, .sup.4J.sub.H-H=1.0 Hz, 1H), 8.15-8.25 (m, 2H), 8.38 (ddd, .sup.3J.sub.H-H=8.0 Hz, .sup.3J.sub.H-H=7.0 Hz, .sup.4J.sub.H-H=1.0 Hz, 1H), 8.73 (d, .sup.3J.sub.H-H=8.0 Hz, 1H), 9.26 (d, .sup.3J.sub.H-H=8.5 Hz, 1H), 9.32 (dd, .sup.3J.sub.H-H=8.0 Hz, .sup.4J.sub.H-H=1.5 Hz, 1H).

[0185] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz): δ 29.7 (d, .sup.3J.sub.C-F=19.6 Hz), 51.3 (d, .sup.3J.sub.C-F=4.9 Hz), 81.0 (d, .sup.1J.sub.C-F=162.3 Hz), 120.67, 120.7 (q, .sup.1J.sub.C-F=320.25 Hz), 123.2, 124.5, 125.6, 126.0, 128.3, 129.3, 130.3, 130.4, 130.9, 131.4, 132.4, 132.6, 133.8, 134.5, 137.4, 164.4.

[0186] .sup.19F NMR ((CD.sub.3).sub.2SO, 470 MHz): δ −77.7 (s, 3F), −220.9 (tt, .sup.2J.sub.F-H=47.1, .sup.3J.sub.F-H=27.3, 1F).

Example 23. 3,6-Bis(dimethylamino)-10-(3-fluoropropyl)acridinium trifluoromethanesulfonate

[0187] 3-Fluoropropropyl trifluoromethanesulfonate (0.167 g, 0.79 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 12 ml DCM is added using a needle and syringe. The solution is cooled to a temperature of −56° C. using a cooling bath (liquid nitrogen+ethyl acetate). A solution of Acridinium Orange (0.168 g, 0.63 mmol) in 12 ml DCM is added dropwise to the cooled solution over about 20 minutes, after which the contents of the flask are stirred for 72 h. At the end of the reaction, the reaction mixture is concentrated to about 12 ml, and 12 ml of cold Et.sub.2O is added. The mixture is left in the refrigerator for 30 min, after which the product is filtered under reduced pressure. 0.339 g of the title compound is obtained (89.7% yield).

[0188] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 2.20 (d, .sup.3J.sub.H-F=28.0, 2H), 3.19 (s, 12H), 4.50-4.80 (m, 4H), 6.48 (s, 2H), 7.12 (d, .sup.3J.sub.H-H=9 Hz, 2H), 7.75 (d, .sup.3J.sub.H-H=9 Hz, 2H), 8.57 (s, 1H).

[0189] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz): δ 26.7 (d, .sup.2J.sub.C-F=19.5 Hz), 40.1, 43.2, 81.7 (d, .sup.1J.sub.C-F=161.3 Hz), 92.0, 114.0, 116.2, 120.7 (q, .sup.1J.sub.C-F=320 Hz), 132.8, 142.0, 142.7, 155.2.

[0190] .sup.19F NMR ((CD.sub.3).sub.2SO, 470 MHz): δ −77.7 (s, 3F), −219.0 (tt, .sup.2J.sub.F-H=49.4 Hz, .sup.3J.sub.H-H25.1 Hz, 1F).

Example 24. 3,6-Bis(dimethyl amino)-10-(6-trifluoromethylsulfonyloxyhexyl)-acridinium trifluoromethanesulfonate

[0191] 1,16-Bis(trifluoromethanesulfonyloxy)hexane (0.434 g, 1.14 mmol) is added to a 50 ml round-bottom single-neck flask with a magnetic dipole. 6 ml DCM is added using a needle and syringe. The solution is cooled to a temperature of −56° C. using a cooling bath (liquid nitrogen+ethyl acetate), and a solution of Acridinium Orange (0.285 g, 1.07 mmol) in 12 ml DCM is added dropwise to the cooled solution over about 20 minutes. The contents of the flask are stirred for 96 h, and at the end of the reaction, 20 ml of cold Et.sub.2O is added. The mixture is left in the refrigerator for 30 min, after which the precipitate formed is filtered off under reduced pressure to obtain 0.370 g of raw product with an estimated content of the title compound of approx. 33% (as determined based on signal integration in the .sup.1H NMR spectrum).

[0192] .sup.1H NMR ((CD.sub.3).sub.2SO, 500 MHz): δ 1.0-2.0 (m, 8H), 3.22 (s, 12H), 4.40 (bs, 2H), 4.53 (bs, 2H), 6.28 (s, 2H), 7.02 (d, J=7.5 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H), 8.43 (s, 1H).

[0193] .sup.13C NMR ((CD.sub.3).sub.2SO, 125 MHz): δ 22.7, 25.0, 29.1, 29.2, 32.4, 46.6, 69.6, 91.8, 113.9, 114.2, 116.4, 132.7, 132.8, 142.4, 155.2.

[0194] .sup.19F NMR ((CD.sub.3).sub.2SO, 470 MHz): δ −77.8 (s, 3F).

Example 25. The Method of Manufacturing .SUP.18.F-Radiolabelled Compounds According to the Disclosure Using the Method Illustrated by the Reaction Sequence According to Scheme I

[0195] .sup.18F-labelled derivatives are synthesised using the Modular Lab Standard (Eckert&Ziegler) synthesiser. The .sup.18F; radioisotope is produced using Siemens Eclipse cyclotron in the .sup.18O (p,n).sup.18F reaction. The resulting .sup.18F.sup.− is deposited on the anion-exchange column QMA, from which water enriched with H.sub.2.sup.18O is recovered. The fluoride compound .sup.18F.sup.− is eluted from the QMA column to the reactor using 600 μl kryptofix solution (22 mg) with potassium carbonate (11.7 mg) using H.sub.2O:ACN eluent (1:1). Solvents are distilled off under reduced pressure, and then residual water is removed through azeotropic distillation by adding 1 ml ACN twice. A precursor, i.e. a quaternary ammonium salt of a polycyclic aromatic amine having a leaving group (preferably a trifluoromethanesulfonate group) in the chain side substituent on the quaternary nitrogen atom (in the amount of 12 to 20 mg) in DCM, is added to the reactor. The reaction is carried out at a temperature of 90° C. for 6.5 to 10 min. The reactor is cooled, and the solution is transferred to a collection vial. The reactor is then washed with a solution of acetate buffer, pH=5.2 supplemented with ethanol (12 to 28.5%), which is also transferred to the collection vial. The collected solution is applied on a semi-preparative HPLC column (250×10 mm, Luna, Phenomenex), using the acetate buffer, pH=5.2, mixed with ethanol as the mobile phase. For the phenanthridine derivative a mobile phase with 12.0% ethanol content is used, for the phenylphenanthridine derivative a mobile phase with 23.5% ethanol content is used, and for the acridine derivative a mobile phase with 28.5% ethanol content is used.

[0196] Based on the tests carried out with the use of standards, a product was obtained through collection of fractions from the semi-preparative column with a specified retention time. For the phenanthridine derivative, the product is collected directly into the final vial, while the acridine and phenylphenanthridine derivatives are transferred to a second reactor to remove excess ethanol through distillation at a temperature of 105-110° C. for 8 to 10 min followed by transferring the product to the final vial. The labelling yield under these conditions is 1-5%.

[0197] The radioisotope-labelled compound according to the disclosure obtained in the form of acetate salt is analysed by high-performance liquid chromatography (HPLC) to confirm the identity (by comparison with the standard provided by a structural analogue of the radioisotope-labelled compound of the quaternary ammonium salt of a polycyclic aromatic amine according to the disclosure, wherein said analogue has a non-radioactive fluorine atom, i.e. .sup.19F, replacing .sup.18F at the corresponding position at R.sup.2 substituent carbon atom) and to determine the level of chemical and/or radiochemical contaminants, if any. The identity of the .sup.18F isotope is confirmed by determining half-life (110 min) and measuring the gamma radiation energy of the .sup.18F isotope (main peak of 511 KeV). In addition, thin-layer chromatography (TLC) is used to determine radiochemical purity.

[0198] The method for manufacturing .sup.18F-radiolabelled compounds according to the disclosure using the method as above also allows for obtaining the product in the form of a salt with a counterion other than the acetate anion. For this purpose, experiments were carried out using a semi-preparative HPLC column (250×10 mm, Luna, Phenomenex) used to obtain .sup.18F-labelled compounds, on which column N-(2-fluoroethyl)-6-phenylphenanthridinium trifluoromethanesulfonate was loaded. Mixtures of acetonitrile and three different buffers of 0.1 M phosphoric acid (pH=2.4), ascorbic acid (pH=6.3) or citric acid (pH=6.3) concentration, respectively, in isocratic system, were used as eluents. Product samples obtained following the elution from the semi-preparative column were analysed by high resolution mass spectrometry to determine the structure of both the cation and anion of the eluted quaternary amine compound in the form of salt. The results of the analyses are summarised in table 1 below.

TABLE-US-00001 TABLE 1 Buffer Phosphate Citrate Ascorbate pH 2.4  6.3  6.3  Phase composition 25:75 27:73 27:73 (ACN %:buffer %) Theoretical mass of the 302.13395 cation MS cation mass 302.13381 302.13381 302.13377 Anion H.sub.2PO.sub.4.sub.− C.sub.6H.sub.7O.sub.7.sub.− C.sub.6H.sub.7O.sub.6.sub.− Theoretical mass of the  96.96852 191.01863 175.02371 anion MS anion mass  96.96807 191.01870 175.02369

[0199] The results obtained clearly demonstrate that depending on the buffer added to the eluent used, the required counterion salt is obtained, and in these specific experiments a compound of quaternary ammonium salt of a polycyclic aromatic amine is obtained, wherein the ammonium cation is accompanied by a dihydrogen phosphate, citrate or ascorbate anion, respectively.

Example 26. Manufacture of a Pharmaceutical Form of the .SUP.18.F-Radiolabelled Compound According to Disclosure

[0200] The synthesis, formulation and dispensing of the preparation are performed in hot chambers. The active ingredient, i.e. the radioisotope-labelled compound of a polycyclic quaternary aromatic amine according to the disclosure, is manufactured and purified in accordance with the procedure presented in the examples above, after which the appropriate pH of the active ingredient solution is determined using a buffer, e.g. citrate, acetate, phosphate buffer (optionally, if not necessary, no buffer is used). If required, a pharmacologically non-aqueous acceptable diluent/solvent is added to the solution (for example to improve solubility or stability, such as ethanol); optionally, the solution is not diluted. The resulting solution is added through a sterilisation filter, for example 0.22 μm in size, to a collection vial placed in a grade A purity isolator, where the final formulation and determination of the desired radioactive concentration is performed by way of dilution (if necessary) of the raw product with a physiological solution of sodium chloride or injection water. The resulting product in bulk is automatically distributed into the final containers (vials, or directly to syringes) through a 0.22 μm final sterilisation filter. Optionally, thermal final sterilisation is used where the thermal treatment does not adversely affect the stability of the product. The vials are placed in external protective shielding.

Example 27. PET-CT Scan Performed Using an Animal Model

[0201] Male rats weighing approx. 250 g are quarantined for a period of no less than 5 days. The animals are anaesthetised in an induction chamber using a 3.5-4% isoflurane (Baxter AErrane) atmosphere. The anaesthetised animal is transferred under an anaesthesis-maintaining mask (1.5-2% isoflurane in the air). A catheter is mounted on the lateral caudal vein of the animal. A heparin solution (approx. 50 μl) is injected into the vein in order to check the patency of the catheter and prevent excessive blood clotting.

[0202] The animal is transferred to a measurement bed placed in a PET/SPECT/CT scanner (Albira Carestream) equipped with a sensor allowing for monitoring the number of breaths and a system providing anaesthesia during the measurement. The number of breaths during the measurement is regulated by the concentration of the isoflurane supplied in the air and maintained within the range of 50-70 breaths per minute. For the duration of the measurement, the eyes of the animal are protected with a protective preparation (Vidisic).

[0203] The animal is administered 100 to 200 μl of the .sup.18F-labelled radiopharmaceutical of the compound according to the disclosure (a cardiotracer) and 100 to 200 μl saline solution (in order to transport as much cardiotracer as possible from the catheter's dead space).

[0204] When the tracer administration is over, the dynamic PET acquisition starts.

[0205] The PET acquisition takes 35 to 90 minutes, depending on the recommendations of the person ordering the scan. The acquisition consists of a sequence of scans with a duration of 30 to 500 s (shorter scans occur in the first phase of the acquisition due to the higher dynamics of changes in the tracer biodistribution).

[0206] After the PET acquisition is over, the test object is moved to the CT module, where the whole body scan is performed (45 kVp tube voltage, 400 mA current, 400 projections per rotation, 4 rotations).

[0207] After the acquisition is over, the animal is awakened from anaesthesia and placed in a cage for 48 h in order to observe whether the tracer administration induced any adverse effects. It is then euthanized or may be used for another experiment, if planned within the next few days.

[0208] The acquisition results are reconstructed into 3D images using the Albira Suite Reconstructor software. An analysis is performed to obtain the specific uptake value (SUV) of the cardiotracer for selected organs and tissues: heart muscle, cardiac blood pool, lungs, liver, kidneys, bladder.

[0209] FIG. 1-3 illustrate representative PET images obtained in the above experimental animal studies: summed (1) and cross-sectional (2-4) in the frontal (1-2), sagittal (3) and transverse (4) plane of radioactivity distribution following the administration of compounds according to the subject disclosure to animals. More specifically, imaging of FIG. 1 was obtained by administering the pharmaceutical form of 5-(2-[.sup.18F]fluoroethyl)phenanthridinium salt, imaging of FIG. 2 was obtained by administering the pharmaceutical form of 6-phenyl-5-(2-[.sup.18F]fluoroethyl)phenanthridinium salt, and imaging of FIG. 3 was obtained by administering the pharmaceutical form of 3,6-bis(dimethylamino)-10-(2-[.sup.18F]fluoroethyl)acridinium salt. The pharmaceutical forms provided in the study were solutions of acetate salts in saline aqueous solution (i.e. cations of the ammonium salts of a polycyclic aromatic amine with formula I according to the disclosure referred to above were accompanied by chloride and acetate anions). The images are presented as the sum of time frames: 2-5 min (A) and 20-35 min (B).

Example 28. Description of the Medical Procedure in Humans

[0210] Patients are placed on their back, with their hands behind their head, in the PET-CT scanner, and an intravenous catheter is placed in the lower part of the upper limb. Imaging begins with a resting scan in a dynamic data collection mode with the injection of a .sup.18F-labelled radiopharmaceutical according to the disclosure. In the next scan, imaging is performed under stress following a pharmacological or physical stress. For dynamic imaging, the data acquisition start time is a few seconds before tracer administration. Perfusion images are acquired for 10 minutes directly following the intravenous tracer bolus administration. The minimum interval between the scan at rest and under stress is 50 minutes. Stress is induced in the patient through physical exercise or pharmacologically by administering regadenosone intravenous bolus (0.4 mg) regardless of body weight for 20-30 s. For regadenosone, the cannula is flushed with 5 ml saline directly after the administration, followed by the administration of a radioisotope-labelled compound according to the disclosure labelled with .sup.18F (cardiotracer) 30 seconds after the saline. The PET scan is carried out as follows: 10 minutes of dynamic scan (12×10 seconds, 4×30 seconds, 1×6 minutes) in the area of the heart with an additional area above and below; 3D data acquisition, ECG gating (8 or 16 frames per cycle); array: 128×128.

[0211] PET imaging is performed at rest and under stress using PET-CT tomographs. With CT scans, attenuation adjustment is achieved 2 minutes before or after the test at rest and under stress. Low-dose CT is performed within 3 minutes before or after the acquisition of dynamic scans. The total CT scan time is 20 seconds. The rotation time of the X-ray tube is 0.5 second at 140 kV and 30 mA. Details of the myocardial perfusion imaging are summarised in table 2.

TABLE-US-00002 TABLE 2 Rest and stress myocardial perfusion imaging Characteristic Imaging parameters Stress conditions Pharmacological agent regadenoson or physical strain Tracer dose (3D) (2-12 MBq/kg) usually 3-4 MBq/kg Delay for static images 1.5-3 minutes after the administration Delay for dynamic Activating the device directly before injecting images the tracer dose PET/CT CT scout Imaging mode ECG-gated imaging of perfusion and functional parameters of the myocardium Mode: gated/dynamic Imaging duration 12-15 minutes Attenuation adjustment Attenuation adjustment measurement before or after the acquisition Reconstruction method Iterative expectation maximisation method (e.g. OSEM) Reconstruction filters Sufficient to achieve the desired resolution/smoothing, matching stress and rest conditions Reconstructed voxel size 3.27