Stabilization of radiosynthetic intermediates

Abstract

The present invention relates to a method for stabilizing radiosynthetic intermediates used in synthesis of .sup.18F radiolabeled aromatic amino acid derivatives toward decomposition caused by beta and gamma radiations by the use of radical scavengers and/or reductants and/or antioxidants.

Claims

1. A method for stabilizing, toward decomposition caused by beta and gamma radiations, cold and radiosynthetic intermediates used in a synthesis of 18F radiolabeled aromatic amino acid derivatives, wherein the starting activity of 18F is in the range 1-30 Ci for a radioactivity concentration from 0.5 to 15 Ci/mL, said synthesis comprising at least the steps of: 1) providing a cold aromatic precursor; 2) fluorinating said cold aromatic precursor with 18F so as to obtain a 18F radiosynthetic intermediate, and modifying said 18F radiosynthetic intermediate, or 2) modifying said cold aromatic precursor so as to obtain a cold aromatic intermediate, and fluorinating said cold aromatic intermediate with 18F, so as to obtain in both cases a modified 18F radiosynthetic intermediate, wherein the step of modifying said cold aromatic precursor or 18F radiosynthetic intermediate is at least one of a reduction, an oxidation, a halogenation reaction, and a substitution reaction of one functional group by another functional group; 3) deprotecting and/or hydrolyzing said modified 18F radiosynthetic intermediate so as to obtain said 18F radiolabeled aromatic amino acid derivative, said cold aromatic precursor, said cold aromatic intermediate, and said modified or not 18F radiosynthetic intermediate having the general structure: ##STR00015## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are selected from the group consisting of H, OH, OMe, OBn, and Oallyl; wherein L is selected from the group consisting of NO.sub.2, NMe.sub.3.sup.+, F, IO.sub.2, ##STR00016##  in the case of a cold aromatic precursor or a cold aromatic intermediate and wherein L is .sup.18F in the case of a modified or not 18F radiosynthetic intermediate; wherein R.sub.5 is selected from the group consisting of OH, I, Br, CI, ##STR00017## with R being COCH.sub.3, COCF.sub.3, CH.sub.2Ph, BOC, or COOCH.sub.2Ph; with R.sub.6 being Me or Ph, and with R.sub.7 being H or CH.sub.3; wherein said stabilizing method comprises a stabilization step of contacting said cold aromatic precursor, said cold aromatic intermediate, and said modified or not 18F radiosynthetic intermediate with one or more compounds being at least one of radical scavengers, reductants, and antioxidants, selected from the group of carbonate (CO.sub.3.sup.2−), nitrite, thiosulfate, thiosulfite, phosphate, phosphite, hypophosphite, phosphorous acid, a Fe(II) derivative, a Sn(II) derivative, iodide, a phenol derivative, HI, toluene, and dichloromethane.

2. A method for stabilizing, toward decomposition caused by beta and gamma radiations, cold and radiosynthetic intermediates used in a synthesis of 18F radiolabeled aromatic amino acid derivatives, said synthesis comprising at least the steps of: 1) providing a cold aromatic precursor; 2) fluorinating said cold aromatic precursor with 18F so as to obtain a 18F radiosynthetic intermediate, and modifying said 18F radiosynthetic intermediate, or 2) modifying said cold aromatic precursor so as to obtain a cold aromatic intermediate, and fluorinating said cold aromatic intermediate with 18F, so as to obtain in both cases a modified 18F radiosynthetic intermediate, wherein the step of modifying said cold aromatic precursor or 18F radiosynthetic intermediate is at least one of a reduction, an oxidation, a halogenation reaction, and a substitution reaction of one functional group by another functional group; 3) deprotecting and/or hydrolyzing said modified 18F radiosynthetic intermediate so as to obtain said 18F radiolabeled aromatic amino acid derivative, said cold aromatic precursor, said cold aromatic intermediate, and said modified or not 18F radiosynthetic intermediate having the general structure: ##STR00018## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are selected from the group consisting of H, OH, OMe, OBn, and Oallyl; wherein L is selected from the group consisting of NO.sub.2, NMe.sub.3.sup.+, F, IO.sub.2, ##STR00019## in the case of a cold aromatic precursor or a cold aromatic intermediate and wherein L is .sup.18F in the case of a modified or not 18F radiosynthetic intermediate; wherein R.sub.5 is selected from the group consisting of OH, I, Br, CI, ##STR00020## with R being COCH.sub.3, COCF.sub.3, CH.sub.2Ph, BOC, or COOCH.sub.2Ph; with R.sub.6 being Me or Ph, and with R.sub.7 being H or CH.sub.3; wherein said stabilizing method comprises a stabilization step of contacting said cold aromatic precursor, said cold aromatic intermediate and said modified or not 18F radiosynthetic intermediate with one or more compounds selected from the group consisting of radical scavengers, reductants, and antioxidants; wherein phosphorous acid is used in the stabilization step of said cold aromatic precursor, said cold aromatic intermediate, and said modified or not 18F radiosynthetic intermediate.

3. A method for stabilizing, toward decomposition caused by beta and gamma radiations, cold and radiosynthetic intermediates used in a synthesis of 18F radiolabeled aromatic amino acid derivatives, said synthesis comprising at least the steps of: 1) providing a cold aromatic precursor; 2) fluorinating said cold aromatic precursor with 18F so as to obtain a 18F radiosynthetic intermediate, and modifying said 18F radiosynthetic intermediate, or 2) modifying said cold aromatic precursor so as to obtain a cold aromatic intermediate, and fluorinating said cold aromatic intermediate with 18F, so as to obtain in both cases a modified 18F radiosynthetic intermediate, wherein the step of modifying said cold aromatic precursor or 18F radiosynthetic intermediate is at least one of a reduction, an oxidation, a halogenation reaction, and a substitution reaction of one functional group by another functional group; 3) deprotecting and/or hydrolyzing said modified 18F radiosynthetic intermediate so as to obtain said 18F radiolabeled aromatic amino acid derivative, said cold aromatic precursor, said cold aromatic intermediate, and said modified or not 18F radiosynthetic intermediate having the general structure: ##STR00021## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are selected from the group consisting of H, OH, OMe, OBn, and Oallyl; wherein L is selected from the group consisting of NO.sub.2, NMe.sub.3.sup.+, F, IO.sub.2, ##STR00022## in the case of a cold aromatic precursor or a cold aromatic intermediate and wherein L is .sup.18F in the case of a modified or not 18F radiosynthetic intermediate; wherein R.sub.5 is selected from the group consisting of OH, I, Br, CI, ##STR00023## with R being COCH.sub.3, COCF.sub.3, CH.sub.2Ph, BOC, or COOCH.sub.2Ph; with R.sub.6 being Me or Ph, and with R.sub.7 being H or CH.sub.3; wherein said stabilizing method comprises a stabilization step of contacting said cold aromatic precursor, said cold aromatic intermediate, and said modified or not 18F radiosynthetic intermediate with one or more compounds selected from the group consisting of radical scavengers, reductants, and antioxidants; wherein a Fe(II) derivative or a Sn(II) derivative is used in the stabilization step of said cold aromatic precursor, said cold aromatic intermediate, and said modified or not 18F radiosynthetic intermediate.

4. The method of claim 1, wherein HI is used in a halogenation step and/or in the deprotection/hydrolysis step.

5. The method of claim 1, wherein the stabilization step occurs after the step of fluorinating said cold aromatic precursor or said cold aromatic intermediate with 18F and/or the step of modifying said 18F radiosynthetic intermediate and/or during the step of deprotecting and/or hydrolyzing said modified 18F radiosynthetic intermediate.

6. The method of claim 1, wherein the compound used in the stabilization step is also involved in the radiosynthetic process as a reagent or as a solvent.

7. The method of claim 1, wherein HI is used both in the stabilization step of the cold and radiosynthetic intermediates as a reagent.

Description

EXAMPLES

(1) In these examples it will be demonstrated how the right choice of the additives and reagents allows to stabilize the yields toward increasing the starting activity.

Example 1

[18F]-FDOPA Synthesis with Lemaire et al. Method and with Eliminating HI in the Crucial Step

(2) ##STR00007##

(3) HI was used for the halogenation and is eliminated by KOH+water rinsing step during the on cartridge process. HI was also used during the deprotection/hydrolysis step. Low activity (˜100 mCi) yield EOS: 30% (n=18). High activity (˜6 Ci) yield EOS: 3% (n=6).

Example 2

[18F]-FDOPA Synthesis with Lemaire et al. Method with HI

(4) ##STR00008##

(5) HI was used for the halogenation and remains present all the time during the on cartridge process. HI was also used during the deprotection/hydrolysis step. Low activity (˜100 mCi) yield EOS: 25% (n=20). High activity (˜6 Ci) yield EOS: 25% (n=10).

Example 3

[18F]-FDOPA Synthesis with Lemaire et al. Method with Replacement of HI with HBr in the Crucial Step

(6) ##STR00009##

(7) HBr was used for the halogenation HI was used during the deprotection/hydrolysis step. Low activity (˜100 mCi) yield EOS: 20% (n=3). High activity (˜3 Ci) yield EOS: 12% (n=2).

Example 4

[18F]-FDOPA Synthesis with Lemaire et al. Method with Replacement of HI with HBr/KI in the Crucial Step

(8) ##STR00010##

(9) HBr was used for the halogenation in mixture with KI. HI was used during the deprotection/hydrolysis step. Low activity (˜100 mCi) yield EOS: 21% (n=3). High activity (˜3 Ci) yield EOS: 19% (n=2).

Example 5

[18F]-FDOPA synthesis with Di Magno et al. method and HBr

(10) ##STR00011##

(11) HBr was used during the deprotection/hydrolysis step. Low activity (˜100 mCi) yield EOS: 18% (n=2). High activity (˜1.5 Ci) yield EOS: 9% (n=1).

Example 6

[18F]-FDOPA Synthesis with Coenen et al. Method and HBr

(12) ##STR00012##

(13) HBr was used during the deprotection/hydrolysis step. Low activity (˜60 mCi) yield EOS: 15% (n=1). High activity (˜3 Ci) yield EOS: 8% (n=1).

Example 7

[18F]FDOPA Synthesis with Coenen et al. Method and HBr/KI

(14) ##STR00013##

(15) HBr/KI was used during the deprotection/hydrolysis step. Low activity (˜50 mCi) yield: 12% (n=1). High activity (˜3 Ci) yield: 11% (n=1).

Example 8

[18F]-FDOPA Synthesis with Lemaire et al. Method and with Eliminating HI in the Crucial Step in the Presence of Sodium Thiosulfate (STS)

(16) ##STR00014##

(17) HI was used for the halogenation and is eliminated by a sodium thiosulfate in water solution rinsing step during the on cartridge process. HI was also used during the deprotection/hydrolysis step. Low activity (˜45 mCi) yield EOS: 23% (n=1). High activity (˜3 Ci) yield EOS: 19% (n=1).