PHOSPHONIUM COMPOUND AND PRODUCTION METHOD THEREFOR

Abstract

The present invention provides a phosphonium compound of formula (II). Also provided is a method for producing a quaternary phosphonium compound labeled with a positron emitting radionuclide, the method comprising the step of reacting an electrophile of formula (I): X.sup.1-CH.sub.2-A.sup.1 with triphenylphosphine having one or more radionuclide-labeled substituents on the benzene ring to give a quaternary phosphonium salt.

Claims

1. A phosphonium compound of formula (II): ##STR00065## wherein Ar.sup.1, Ar.sup.2, and Ar.sup.3 are each independently an aryl optionally substituted with one or more substituents selected from B.sup.2, wherein at least one of Ar.sup.1, Ar.sup.2, and Ar.sup.3 is substituted with one or more substituents selected from radionuclide-labeled C.sub.1-6alkyl, radionuclide-labeled C.sub.2-6alkoxy, radionuclide-labeled C.sub.2-6alkoxyC.sub.1-6alkyl, radionuclide-labeled C.sub.2-6alkoxyC.sub.2-6alkoxy, radionuclide-labeled C.sub.2-6alkoxyC.sub.2-6alkoxyC.sub.1-6alkyl, and radionuclide-labeled C.sub.2-6alkoxyC.sub.2-6alkoxyC.sub.2-6alkoxy; A.sup.1 is a hydrogen atom, C.sub.1-10alkyl optionally substituted with one or more substituents selected from B.sup.1, C.sub.2-10alkenyl optionally substituted with one or more substituents selected from B.sup.1, or an aryl optionally substituted with one or more substituents selected from B.sup.2; each B.sup.1 is independently a halogen atom, C.sub.1-6alkoxy, phenyl, or naphthyl, wherein the phenyl and naphthyl are optionally substituted with one or more substituents selected from C.sub.1-6alkyl, C.sub.1-6alkoxy, and halogen atoms; each B.sup.2 is independently a halogen atom, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkylthio, cyano, amino, C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, nitro, hydroxy, or (C.sub.1-3alkoxy)carbonyl, wherein the alkyl, alkoxy and alkylthio are optionally substituted with one or more substituents selected from halogen atoms; Ar.sup.1, Ar.sup.2, Ar.sup.3 and A.sup.1, and the substituents contained therein, optionally form acid addition salts; X.sup. is an anion with a total charge of 1.

2. The phosphonium compound according to claim 1, wherein the radionuclide is a positron emitting nuclide.

3. The phosphonium compound according to claim 2, wherein the positron emitting nuclide is .sup.18F.

4. The phosphonium compound according to claim 1, wherein A.sup.1 is a hydrogen atom, C.sub.1-6alkyl optionally substituted with one or more halogen atoms, phenyl, or phenylC.sub.1-4alkyl, wherein the phenyl or a phenyl moiety of phenylC.sub.1-4alkyl is optionally substituted with one or more substituents selected from one or more halogen atoms, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkylthio, cyano, amino, C.sub.1-6alkylamino, di(C.sub.1-6alkyeamino, nitro, hydroxy, and (C.sub.1-3alkoxy)carbonyl.

5. The phosphonium compound according to claim 1, wherein the phosphonium compound comprises a phosphonium selected from: benzyl-[4-(2-[.sup.18F]fluoroethoxy)phenyl]-diphenylphosphonium; benzyl-(4- [2- {2-(2-[.sup.18F]fluoroethoxy)ethoxy}ethoxy]phenyl)-diphenylphosphonium; [4-(2-[.sup.18F]fluoroethoxy)phenyl]-(4-methoxycarbonylphenyl)methyl-diphenylphosphonium; [4-(2-[.sup.18F]fluoroethoxy)phenyl]-(4-fluorophenyemethyl-diphenylphosphonium; [4-(2-[.sup.18F]fluoroethoxy)phenyl]-(3,4,5-trifluorophenyl)methyl-diphenylphosphonium; (4-chlorophenypmethyl-[4-(2-[.sup.18F]fluoroethoxy)phenyl]-diphenylphosphonium; [4-(2-[.sup.18F]fluoroethoxy)phenyl]-(4-methoxyphenyl)methyl-diphenylphosphonium; [4-(2-[.sup.18F]fluoroethoxy)phenyl]-(n-pentyl)-diphenylphosphonium; [4-(2-[.sup.18F]fluoroethoxy)phenyl]-(3-phenylpropyl)-diphenylphosphonium; (4-n-butylphenyl)methyl-[4-(2-[.sup.18F] fluoroethoxy)phenyl]-diphenylphosphonium; (3 -fluorophenyl)methyl-[4-(2-[.sup.18F] fluoroethoxy)phenyl]-diphenylphosphonium; [4-(2-[.sup.18F] fluoroethoxy)phenyl[-]4-(trifluoromethylthio)phenyl]methyl-diphenylpho sphonium; [4-(2-[.sup.18F] fluoroethoxy)phenyl]-(2-methylphenyl)methyl-diphenylphosphonium; (3-cyanophenyl)methyl-[4-(2-[.sup.18F]fluoroethoxy)phenyl]-diphenylphosphonium; [4-(2-[.sup.18F]fluoroethoxy)phenyl]-methyl-diphenylphosphonium; allyl-[4-(2-[.sup.18F]fluoroethoxy)phenyl]-diphenylphosphonium; benzyl- [3-(2-[.sup.18F]fluoroethoxy)phenyl]-diphenylphosphonium; [3 -(2-[.sup.18F]fluoroethoxy)phenyl]-(4-methoxyphenyemethyl-diphenylphosphonium; [3 -(2- [.sup.18F]fluoroethoxy)phenyl]-(4-methoxycarbonylphenyemethyl-diphenylphosphonium; [3 -(2-[.sup.18F]fluoroethoxy)phenyl]-(4-fluorophenyl)methyl-diphenylphosphonium; [3 -(2-[.sup.18F]fluoroethoxy)phenyl]-(3-phenylpropyl)-diphenylphosphonium; (4-chlorophenyl)methyl- [3 -(2-[.sup.18F]fluoroethoxy)phenyl]-diphenylphosphonium; [3 -(2-[.sup.18F]fluoroethoxy)phenyl]-(3,4,5-trifluorophenyl)methyl-diphenylphosphonium; benzyl-[3-(3-[.sup.18F]fluoropropoxy)phenyl]-diphenylphosphonium; benzyl-[3-(4-[.sup.18F] fluorobutoxy)phenyl]-diphenylphosphonium; [3 -(2- [.sup.18F]fluoroethoxy)phenyl]-methyl-diphenylphosphonium; and benzyl[2-(2-[4.sup.18F]fluoroethoxy)phenyl]-diphenylphosphonium.

6. The phosphonium compound according to claim 1, wherein the phosphonium compound is selected from: benzyl-[4-(2-[.sup.18F]fluoroethoxy)phenyl]-diphenylphosphonium bromide; benzyl-[3-(2-[.sup.18F]fluoroethoxy)phenyl]-diphenylphosphonium bromide; [3 -(2- [.sup.18F]fluoroethoxy)phenyl]-(4-methoxyphenyl)methyl-diphenylphosphonium bromide; and [3-(2-[.sup.18F]fluoroethoxy)phenyl]-(3 -phenylpropyl)-diphenylphosphonium bromide.

7. A radiopharmaceutical for use in imaging, comprising the phosphonium compound according to claim 1.

8. A radiopharmaceutical for use in PET imaging, comprising the phosphonium compound according to claim 2.

9. The radiopharmaceutical according to claim 8, for use in mitochondrion imaging.

10. The radiopharmaceutical according to claim 8, for use in imaging of myocardium, tumor, or brown adipose tissue.

11. A disposable product comprising the radiopharmaceutical according to claim 7.

12. A method for producing a quaternary phosphonium compound labeled with a radionuclide, the method comprising the step of: reacting an electrophile of formula (I): X.sup.1-CH.sub.2-A.sup.1 with triphenylphosphine having one or more radionuclide-labeled substituents on the benzene ring to give a quaternary phosphonium salt; wherein X.sup.1 is a leaving group; A.sup.1 is a hydrogen atom, C.sub.1-10alkyl optionally substituted with one or more substituents selected from B.sup.1, C.sub.2-10alkenyl optionally substituted with one or more substituents selected from B.sup.1, or an aryl optionally substituted with one or more substituents selected from B.sup.2; each B.sup.1 is independently a halogen atom, C.sub.1-6alkoxy, phenyl, or naphthyl, wherein the phenyl and naphthyl are optionally substituted with one or more substituents selected from C .sub.1-6alkyl, C.sub.1-6alkoxy, and halogen atoms; each B.sup.2 is independently a halogen atom, C.sub.1-6alkyl, C.sub.1-6alkoxy, cyano, amino, C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, nitro, hydroxy, or (C.sub.1-3alkoxy)carbonyl, wherein the alkyl, alkoxy and alkylthio are optionally substituted with one or more substituents selected from halogen atoms; wherein the one or more radionuclide-labeled substituents are selected from radionuclide-labeled C.sub.1-6alkyl, radionuclide-labeled C.sub.2-6alkoxy, radionuclide-labeled C.sub.2-6alkoxyC.sub.1-6alkyl, radionuclide-labeled C.sub.2-6alkoxyC.sub.2-6alkoxy, radionuclide-labeled C.sub.2-6alkoxyC.sub.2-6alkoxyC.sub.1-6alkyl, and radionuclide-labeled C.sub.2-6alkoxyC.sub.2-6alkoxyC.sub.2-6alkox.sub.Y; wherein the triphenylphosphine optionally further has one or more substituents selected from B.sup.2 on the benzene ring.

13. The method according to claim 12, wherein the radionuclide is a positron emitting nuclide.

14. The method according to claim 13, wherein the positron emitting nuclide is .sup.18F.

15. The method according to claim 12, wherein X.sup.1 is a halogen atom, optionally substituted C.sub.1-6alkylsulfonyloxy, or optionally substituted phenylsulfonyloxy.

16. The method according to claim 12, wherein the method is performed in an automatic synthesizer.

17. A phosphine compound of formula (III): ##STR00066## wherein Ar.sup.1, Ar.sup.2, and Ar.sup.3 are as defined in claim 1.

18. The phosphine compound according to claim 17, wherein the radionuclide is .sup.18F.

19. The phosphonium compound according to claim 1, wherein the radionuclide is replaced with a non-radioactive identical element.

20. A phosphonium compound obtained by replacing .sup.18F in the .sup.18F-labeled phosphonium compound according to claim 3, with .sup.19F.

21. A phosphine compound of formula (III): ##STR00067## wherein Ar.sup.1, Ar.sup.2, and Ar.sup.3 are each independently an aryl optionally substituted with one or more substituents selected from B.sup.2; wherein at least one of Ar.sup.1, Ar.sup.2, and Ar.sup.3 is substituted with one or more substituents selected from: C.sub.1...sub.6alkyl optionally substituted with one or more substituents selected from L, C.sub.2-6alkoxy optionally substituted with one or more substituents selected from L, C.sub.2-6alkoxyC.sub.1-6alkyl optionally substituted with one or more substituents selected from L, C.sub.2-6alkoxyC.sub.2-6alkoxy optionally substituted with one or more substituents selected from L, C.sub.2-6alkoxyC.sub.2-6alkoxyC.sub.1-6alkyl optionally substituted with one or more substituents selected from L, and C.sub.2-6alkoxyC.sub.2-6alkoxyC.sub.2-6alkoxy optionally substituted with one or more substituents selected from L; B.sup.2 is a halogen atom, C.sub.1-6alkyl, C.sub.1-6alkoxy, cyano, amino, C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, nitro, hydroxy, or (C.sub.1-3alkoxy)carbonyl, wherein the alkyl, alkoxy, and alkylthio are optionally substituted with one or more substituents selected from halogen atoms; L is bromine, iodine, p-toluenesulfonyloxy, methanesulfonyloxy, chloromethanesulfonyloxy, or trifluoromethanesulfonyloxy.

22.-24. (canceled)

25. A method for conducting PET scans or image analysis comprising: administering an effective amount of a phosphonium compound according to claim 1 to a subject in need thereof; and conducting PET scans or image analysis of the subject.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0103] FIG. 1 shows the results of preparative HPLC of [.sup.18F]TAP-001 synthesized in Example 1.

[0104] FIG. 2 shows the mouse PET/CT images taken with the labeled compounds of the present invention.

[0105] FIG. 3 shows the graphs of the results of the biodistribution study conducted with the labeled compounds of the present invention.

[0106] FIG. 4 shows the graph of the results of the biodistribution study conducted with the labeled compound of the present invention.

[0107] FIG. 5 shows the PET images taken at time points from 0 to 60 minutes after administration for the purpose of conducting myocardial imaging analysis in rats using the labeled compound of the present invention.

DESCRIPTION OF EMBODIMENTS

[0108] Hereunder, the present invention will be more specifically described.

[0109] According to one aspect of the present invention, there is provided a method for producing a quaternary phosphonium compound labeled with a positron emitting nuclide, the method comprising the step of reacting an electrophile of formula (I) given above with triphenylphosphine substituted with a positron emitting nuclide-labeled substituent.

[0110] As referred to herein, the term aryl refers to an aromatic hydrocarbon ring group having 6 to 14 carbon atoms. Examples of aryl include, but are not limited to, phenyl, 1-naphthyl, and 2-naphthyl.

[0111] As referred to herein, the term C.sub.1-10alkyl refers to a straight-chain, branched-chain, cyclic or partially cyclic alkyl group having 1 to 10 carbon atoms. Examples of C.sub.1-10alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopropylmethyl, and other examples include, but are not limited to, C.sub.1-6alkyl, C.sub.1-4alkyl and C.sub.1-3alkyl.

[0112] As referred to herein, the term C.sub.1-6alkyl refers to a straight-chain, branched-chain, cyclic or partially cyclic alkyl group having 1 to 6 carbon atoms. Examples of C.sub.1-6alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopropylmethyl, and other examples include, but are not limited to, C.sub.1-4alkyl and C.sub.1-3alkyl.

[0113] As referred to herein, the term C.sub.2-10alkenyl refers to a straight-chain, branched-chain, cyclic or partially cyclic alkenyl group having 2 to 10 carbon atoms, and this alkenyl group may contain one double bond or may contain two or more double bonds. Examples of this alkenyl group include, but are not limited to, vinyl, 1-propenyl, 2-propenyl(allyl), 1-butenyl, 2-butenyl, and 3-butenyl, and other examples include, but are not limited to,

[0114] C.sub.2-6alkenyl, C.sub.24alkenyl, and C.sub.2-3alkenyl.

[0115] As referred to herein, the term C.sub.1-6alkoxy refers to the alkyloxy group [O(C.sub.1-6alkyl)] having, as an alkyl moiety, the above-defined alkyl group with 1 to 6 carbon atoms. Examples of C.sub.1-6alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentyloxy, cyclohexyloxy, and cyclopropylmethyloxy, and other examples include, but are not limited to, C.sub.1-4alkoxy and C.sub.1-3alkoxy. As referred to herein, the term C.sub.1-4alkoxy includes, but is not limited to, C.sub.1-3alkoxy.

[0116] As referred to herein, the term C.sub.2-6alkoxy refers to the alkyloxy group [O(C.sub.2-6alkyl)] having, as an alkyl moiety, an alkyl group with 2 to 6 carbon atoms. Examples of C.sub.2-6alkoxy include, but are not limited to, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentyloxy, cyclohexyloxy, and cyclopropylmethyloxy, and other examples include, but are not limited to, C.sub.1-4alkoxy and C.sub.1-3alkoxy.

[0117] As referred to herein, the term C.sub.1-6alkylthio refers to the alkylthio group [S(C.sub.1-6alkyl)] having, as an alkyl moiety, the above-defined alkyl group with 1 to 6 carbon atoms. Examples of C.sub.1-6alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, s-butylthio, i-butylthio, t-butylthio, n-pentylthio, 3-methylbutylthio, 2-methylbutylthio, 1-methylbutylthio, 1-ethylpropylthio, n-hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3-ethylbutylthio, cyclopentylthio, cyclohexylthio, and cyclopropylmethylthio, and other examples include, but are not limited to, C.sub.1-4alkylthio and C.sub.1-3alkylthio. As referred to herein, the term C.sub.1-4alkylthio includes, but is not limited to, C.sub.1-3alkylthio.

[0118] As referred to herein, the term amino refers to NH.sub.2, and may form an acid addition salt in the molecule.

[0119] As referred to herein, the term C.sub.1-6alkylamino refers to the alkylamino group [NH(C.sub.1-6alkyl)] having, as an alkyl moiety, the above-defined alkyl group with 1 to 6 carbon atoms. Examples of C.sub.1-6alkylamino include, but are not limited to, methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, i-butylamino, t-butylamino, n-pentylamino, 3-methylbutylamino, 2-methylbutylamino, 1-methylbutylamino, 1-ethylpropylamino, n-hexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3-ethylbutylamino, cyclopentylamino, cyclohexylamino, and cyclopropylmethylamino, and other examples include, but are not limited to, C.sub.1-4alkylamino and C.sub.1-3alkylamino. As referred to herein, the term C.sub.1-4alkylamino includes, but is not limited to, C.sub.1-3alkylamino. The C.sub.1-6alkylamino group may form an acid addition salt in the molecule.

[0120] As referred to herein, the term di(C.sub.1-6alkyl)amino refers to the alkylamino group [N(C.sub.1-6alkyl).sub.2] having, as an alkyl moiety, the above-defined alkyl group with 1 to 6 carbon atoms. The two alkyl groups can be the same or different. Examples of di(C.sub.1-6alkyl)amino include, but are not limited to, dimethylamino, diethylamino, ethyl(methyl)amino, methyl(n-propyl)amino, ethyl(n-propyl)amino, methyl(i-propyl)amino, ethyl(i-propyl)amino, di(n-propyl)amino, and di(i-propyl)amino, and other examples include, but are not limited to, di(C.sub.1-4alkyl)amino and di(C.sub.1-3alkyl)amino. As referred to herein, the term di(C.sub.1-4alkyl)amino includes, but is not limited to, di(C.sub.1-3alkyl)amino. The di(C.sub.1-6alkyl)amino group may form an acid addition salt in the molecule.

[0121] As referred to herein, the term C.sub.1-6alkoxycarbonyl refers to an alkoxycarbonyl group having, as an alkoxy moiety, the above-defined C.sub.1-6alkoxy group. Examples of C.sub.1-6alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl, as well as C.sub.1-3alkoxycarbonyl.

[0122] As referred to herein, the term C.sub.1-3alkoxycarbonyl refers to an alkoxycarbonyl group having, as an alkoxy moiety, the above-defined C.sub.1-3alkoxy group. Examples of C.sub.1-3alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and isopropoxycarbonyl.

[0123] As referred to herein, the term C.sub.2-6alkoxyC.sub.1-6alkyl refers to a group of the formula (C.sub.1-6alkylene)O(C.sub.2-6alkyl), and examples include, but are not limited to, ethoxymethyl, 2-ethoxyethyl, 2-ethoxypropyl, and 3-ethoxypropyl. Examples of .sup.18F-labeled C.sub.2-6alkoxyC.sub.1-6alkyl include, but are not limited to, CH.sub.2OCH.sub.2CH.sub.2.sup.18F, and CH.sub.2CH.sub.2OCH.sub.2CH.sub.2.sup.18F.

[0124] As referred to herein, the term C.sub.2-6alkoxyC.sub.2-6alkoxy refers to a group of the formula O(C.sub.2-6alkylene)O(C.sub.2-6alkyl), and examples include, but are not limited to, 2-ethoxyethoxy, 2-ethoxypropoxy, and 3-ethoxypropoxy. Examples of .sup.18F-labeled C.sub.2-6alkoxyC.sub.2-6alkoxy include, but are not limited to, OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2.sup.18F.

[0125] As referred to herein, the term C.sub.2-6alkoxyC.sub.2-6alkoxyC.sub.1-6alkyl refers to a group of the formula (C.sub.1-6alkylene)O(C.sub.2-6alkylene)O(C.sub.2-6alkyl), and examples include, but are not limited to, (2-ethoxyethoxy)methyl, 2-(2-ethoxyethoxy)ethyl, 2-(2-ethoxyethoxy)propyl, and 3-(2-ethoxyethoxy)propyl. Examples of .sup.18F-labeled C.sub.2-6alkoxyC.sub.2-6alkoxyC.sub.1-6alkyl include, but are not limited to, CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2.sup.18F, and CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2.sup.18F.

[0126] As referred to herein, the term C.sub.2-6alkoxyC.sub.2-6alkoxyC.sub.2-6alkoxy refers to a group of the formula O(C.sub.2-6alkylene)O(C.sub.2-6alkylene)O(C.sub.2-6alkyl), and examples include, but are not limited to, 2-(2-ethoxyethoxy)ethoxy, 2-(2-ethoxyethoxy)propoxy, and 3-(2-ethoxyethoxy)propoxy. Examples of .sup.18F-labeled C.sub.2-6alkoxy C.sub.2-6alkoxyC.sub.2-6alkoxy include, but are not limited to, OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2.sup.18F.

[0127] As referred to herein, the term optionally substituted C.sub.1-6alkylsulfonyloxy can be exemplified by methanesulfonyloxy, and trifluoromethanesulfonyloxy.

[0128] As referred to herein, the term optionally substituted phenylsulfonyloxy can be exemplified by benzenesulfonyloxy, and toluenesulfonyloxy.

[0129] Examples of halogen atoms include, but are not limited to, fluorine atom, chlorine atom, bromine atom, and iodine atom.

[0130] When the compound of the present invention can form a solvate such as hydrate, this invention can be practiced as a solvate. Further, the compound of the present invention can be practiced, as appropriate, in the form of mixture, solution, polymorph, or the like.

[0131] Examples of X.sup.1 as defined herein include, but are not limited to, chlorine atom, bromine atom, iodine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, and toluenesulfonyloxy.

[0132] In one mode of the phosphonium compound of formula (II), Ar.sup.1, Ar.sup.2 and Ar.sup.3 are each independently a phenyl optionally substituted with one or more substituents selected from B.sup.2.

[0133] In one mode of the phosphonium compound of formula (II), Ar.sup.1 and Ar.sup.2 are each a phenyl, and Ar.sup.3 is a phenyl optionally substituted with one or more substituents selected from B.sup.2.

[0134] In one mode of the phosphonium compound of formula (II), A.sup.1 is a hydrogen atom, C.sub.1-10alkyl optionally substituted with one or more substituents selected from B.sup.1, C.sub.2-10alkenyl optionally substituted with one or more substituents selected from B.sup.1, or a phenyl optionally substituted with one or more substituents selected from B.sup.2.

[0135] The anion (X) contained in the phosphonium compound is for example an anion that forms a pharmaceutically acceptable salt, and specific examples include, but are not limited to, Cl.sup., Br.sup., I.sup., PhSO.sub.2O.sup., CH.sub.3C.sub.6H.sub.4SO.sub.2O.sup., and CH.sub.3SO.sub.2O.sup.. In one mode, X.sup.may be an anion that is generated by the elimination of a leaving group X.sup.1 during reaction.

[0136] Examples of the leaving group as defined herein include, but are not limited to, halogen atoms, optionally substituted C.sub.1-6alkylsulfonyloxy, or optionally substituted phenylsulfonyloxy, and preferred examples include, but are not limited to, bromine atom, iodine atom, p-toluenesulfonyloxy, methanesulfonyloxy, chloromethanesulfonyloxy, and trifluoromethanesulfonyloxy.

[0137] Examples of the leaving group defined herein as L or X.sup.1 include, but are not limited to, halogen atoms, optionally substituted C.sub.1-6alkylsulfonyloxy, or optionally substituted phenylsulfonyloxy, and preferred examples include, but are not limited to, bromine atom, iodine atom, p-toluenesulfonyloxy, methanesulfonyloxy, chloromethanesulfonyloxy, and trifluoromethanesulfonyloxy.

[0138] In formula (II), Ar.sup.1, Ar.sup.2, Ar.sup.3 and A.sup.1, and the substituents contained therein, when containing an amino group, an alkylamino group or a dialkylamino group, may form acid addition salts.

[0139] As used herein, the phrase substituted with one or more substituents means substitution with, for example, 1 to 3 substituents.

[0140] The phosphonium compound of the present invention can be contained in a variety of solutions such as aqueous solution, a variety of solvents such as hydrate, polymorphs, and the like.

[0141] The compound of the present invention can be labeled with a radionuclide by a known method. Examples of the radionuclide include, but are not limited to: .sup.3H, .sup.14C, .sup.35S, and .sup.131I; ray emitting nuclides such as .sup.99mTc, .sup.111In, .sup.67Ga, .sup.201Tl, .sup.123I and .sup.133Xe; and positron emitting nuclides such as .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.62Cu, .sup.64Cu, .sup.68Ga and .sup.76Br. Compounds labeled with a -ray emitting nuclide can be used as imaging agents for computed tomography (Single photon emission computed tomography: SPECT)for example, compounds labeled with .sup.99mTc and .sup.123I are commonly used for SPECT. Compounds labeled with a positron emitting nuclide can be used as imaging agents for positron emission tomography (PET). Among different positron emitting nuclides, .sup.11C, .sup.13N, .sup.15O and .sup.18F are preferred, with .sup.18F and .sup.11C being more preferred, and .sup.18F being particularly preferred, from various viewpoints including appropriate half-life and ease of labeling.

[0142] The phosphonium moiety of the phosphonium compound of formula (II) can be exemplified by the following.

##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008##

[0143] The reaction of an electrophile of formula (I) with triphenylphosphine having one or more positron emitting nuclide-labeled substituents on the benzene ring can be performed by, for example, following the step represented by the scheme given below.

##STR00009##

[0144] [As used in this scheme, Ar.sup.1, Ar.sup.2, Ar.sup.3, X.sup.1, A.sup.1, X.sup. are as defined hereinabove.]

[0145] The aforementioned reaction can be effected by performing heating (at a temperature of, for example, 50-150 C., specifically 90-120 C., more specifically 105-115 C.) in the presence of an appropriate solvent (e.g., acetonitrile, DMSO, DMF, toluene, xylene). The reaction period can be set to be in the range of, for example, 5-60 minutes. This reaction can be performed, for example, under pressure by heating in a sealed container.

[0146] The production method of the present invention, together with preparation of a labeled precursor, can be performed according to the scheme given below.

##STR00010##

[0147] [As used in this scheme, Ar.sup.2, Ar.sup.3, X.sup.1, A.sup.1 and X.sup. are as defined hereinabove; n is an integer selected from 1 to 4; R.sup.1 is a group selected from B.sup.2 defined above; A.sup.2 is selected from (C.sub.1-6alkylene)-, (C.sub.1-6alkylene)O(C.sub.2-6alkylene)-, (C.sub.1-6alkylene)O(C.sub.2-6alkylene)O(C.sub.2-6alkylene)-, O(C.sub.2-6alkylene)-, O(C.sub.2-6alkylene)O(C.sub.2-6alkylene)-, and O(C.sub.2-6alkylene)O(C.sub.2-6alkylene)O(C.sub.2-6alkylene)-; X.sup.2 is a leaving group.]

[0148] As [.sup.18F]KF used at the first step of fluorination, there can be used an aqueous solution of [.sup.18F]KF/K.sub.2CO.sub.3 which is obtained by, for example, irradiating [.sup.18O]H.sub.2O with a proton beam using a cyclotron to thereby generate .sup.18F.sup. and reacting .sup.18F.sup. with K.sub.2CO.sub.3. The [.sup.18F] fluorination reaction can be effected by performing heating (at a temperature of, for example, 80-150 C., specifically 100-120 C., more specifically 110 C.) in the presence of an appropriate solvent (e.g., acetonitrile, DMSO, DMF, DMA). The reaction period can be set to be in the range of, for example, 5-60 minutes, specifically 5-20 minutes, and more specifically set to 10 minutes. This reaction can be performed, for example, under pressure by heating in a sealed container. At the fluorination step, an additive like [2,2,2] cryptand (1,10-diaza-4,7,13,16,24,24-hexaoxabicyclo[8.8.8]hexacosane, Kryptofix [2,2,2]) can be used to improve reaction efficiency. The aforementioned fluorination step can be performed by, for example, the following procedure: an aqueous solution of [.sup.18F]KF/K.sub.2CO.sub.3 and [2,2,2]cryptand are azeotropically dried to give solids, a solution of phosphine serving as a substrate is added to the solids, and then the contents are heated under sealing.

[0149] The leaving group (X.sup.2) used at the aforementioned step is a halogen atom, optionally substituted C.sub.1-6alkylsulfonyloxy, or optionally substituted phenylsulfonyloxy, and preferred examples include, but are not limited to, bromine atom, iodine atom, p-toluenesulfonyloxy, methanesulfonyloxy, chloromethanesulfonyloxy, and trifluoromethanesulfonyloxy.

[0150] The second step can be performed by the same procedure as scheme A. The two steps of scheme B can be performed in a one-pot reaction: for example, after completion of the fluorination reaction, an electrophilic reagent is added to the reaction system without posttreatment and the contents are heated under sealing to obtain a product of interest.

[0151] Purification of a product of interest can be conducted by a common method: for example, purification can be done using preparative HPLC based on radiation intensity. Alternatively, purification can also be done easily using a small disposable column cartridge (Sep-Pak) or the like.

[0152] The imaging agent of the present invention can be prepared by dissolving or suspending the positron emitting nuclide-labeled quaternary phosphonium compound into physiological saline or the like. The imaging agent may contain any additives such as pH adjustor, resolvent, dispersant, solubilizer, and radical scavenger (radiolysis inhibitor) depending on the need.

[0153] The dose of the imaging agent of this invention can be selected, as appropriate, depending on various factors including the organ to be imaged and the body shape of a subject (patient). The imaging agent of this invention can comprise a therapeutically and/or prophylactically effective amount of the compound of formula (I) given above. In this invention, the compound of formula (I) can be generally used at a dose of 0.001 mg/body kg.

[0154] The imaging agent of the present invention can be used for detection of tumor cells by PET and monitoring of the circulatory system, especially the myocardium. Therefore, the inventive imaging agent can be used for the purposes of: examination of tumors such as brain tumor, head and neck cancer, lung cancer and liver cancer; and diagnosis of ischemic heart diseases such as angina pectoris, myocardial infarction, arteriosclerosis of coronary artery, etc., and myocardial ischemia.

EXAMPLES

[0155] Hereunder, the present invention will be described in more detail by way of working examples, but this invention is not limited to these examples. Additionally, in the Hi-flash silica column chromatography conducted for purification of the compounds synthesized in the working examples given below, the flash chromatography system YFLC-AI-700 and the Hi-flash columns (silica gel) produced by Yamazen Corporation were used. Mass spectroscopy was done using JMS-700 produced by JEOL Ltd. or LCMS-2020 produced by Shimadzu Corporation. High performance liquid chromatography (HPLC) was done using the LC-2000Plus system produced by JASCO Corporation.

Synthesis Example 1

4-Diphenylphosphanyl Phenol

[0156] ##STR00011##

[0157] A reaction vessel was charged with 4-iodophenol (5.90 g, 26.9 mmol), potassium acetate (3.17 g, 32.3 mmol), palladium acetate (II) (36.0 mg, 0.6 mol %), and N,N-dimethylacetamide (27 mL), and while the contents were stirred, diphenylphosphine (4.63 mL, 26.9 mmol) was dropwise added slowly. Then, the reaction vessel was heated to 130 C., and reaction was effected for 2 hours. After the reaction, water was added to the reaction system, and the product was extracted three times with CH.sub.2Cl.sub.2 into the organic layer. The resulting organic layer was washed with saturated saline and dried with MgSO.sub.4. After concentration under reduced pressure, the concentrate was purified by Hi-flash silica column chromatography (developing solvent, AcOEt:hexane=11:89.fwdarw.32:68) to yield a product (6.74 g (24.2 mmol), 90% yield, white solid).

[0158] .sup.1H-NMR (600 MHz, CDCl.sub.3):7.36-7.15 (m, 12H), 6.82 (d, J=7.8 Hz, 2H), 5.01 (s, 1H);

[0159] LRMS (EI) calculated for C.sub.18H.sub.15OP (M.sup.t): 278.1, found: 278.1.

Synthesis Example 2

Toluene-4-sulfonic acid 2-(4-diphenylphosphanyl-phenoxy)-ethyl ester

[0160] ##STR00012##

[0161] A reaction vessel was charged with 4-diphenylphosphanyl phenol (434 mg, 1.56 mmol), 1,2-bis(tosyloxy)ethane (2.89 g, 7.80 mmol), potassium carbonate (431 mg, 3.12 mmol), and N,N-dimethylformamide (DMF, 5 mL). The reaction vessel was heated to 50 C., and reaction was effected for 19 hours. After the reaction, water and ethyl acetate were added to the reaction system, unreacted 1,2-bis(tosyloxy)ethane was removed by filtration, and then the product was extracted three times with ethyl acetate into the organic layer. The resulting organic layer was washed with saturated saline and dried with MgSO.sub.4. After concentration under reduced pressure, the concentrate was separated by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=22:78.fwdarw.43:57) to yield a product (587 mg (1.23 mmol), 79% yield, white solid).

[0162] .sup.1H-NMR (600 MHz, CDCl.sub.3): 67.81 (d, J=7.8 Hz, 2H), 7.34-7.31 (m, 8H), 7.29-7.21 (m, 6H), 6.77 (d, J=7.8 Hz, 2H), 4.38-4.35 (m, 2H), 4.16-4.14 (m, 2H), 2.43 (s, 3H);

[0163] LRMS (EI) calculated for C.sub.27H.sub.25O.sub.4PS (M.sup.+): 476.1, found: 476.1.

Synthesis Example 3

2-Diphenylphosphanyl Phenol

[0164] ##STR00013##

[0165] The same synthesis procedure as in Synthesis Example 1 was performed except that 4-iodophenol was replaced by 2-iodophenol. Separation was done by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=18:82.fwdarw.39:61) to yield a product (53% yield, white solid).

[0166] .sup.1H-NMR (600 MHz, CDCl.sub.3):7.38-7.28 (m, 11H), 7.00-6.87 (m, 3H), 6.16 (d, J=6.6, Hz, 1H);

[0167] LRMS (EI) calculated for C.sub.18H.sub.15OP (M.sup.+): 278.1, found: 278.1.

Synthesis Example 4

Toluene-4-sulfonic acid 2-(2-diphenylphosphanyl-phenoxy)-ethyl ester

[0168] ##STR00014##

[0169] The same synthesis procedure as in Synthesis Example 2 was performed using compound 5 as a starting material. Separation was done by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=22:78.fwdarw.43:57) to yield a product (36% yield, white solid).

[0170] LRMS (EI) calculated for C.sub.27H.sub.25O.sub.4PS (M.sup.+): 476.1, found: 476.0.

Synthesis Example 5

3-Diphenylphosphanyl Phenol

[0171] ##STR00015##

[0172] The same synthesis procedure as in Synthesis Example 1 was performed except that 4-iodophenol was replaced by 3-iodophenol. Separation was done by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=12:88.fwdarw.33:67) to yield a product (47% yield, white solid).

[0173] .sup.1H-NMR (600 MHz, CDCl.sub.3):7.37-7.28 (m, 10H), 7.22 (td, J=7.8, 1.8 Hz, 1H), 6.90 (t, J=7.8 Hz, 1H), 6.81 (dd, J=7.8, 2.4 Hz, 1H), 6.70 (dt, J=7.2, 1.2 Hz, 1H), 4.82 (s, 1H);

[0174] LRMS (EI) calculated for C.sub.18H.sub.15OP (M.sup.+): 278.1, found: 278.1.

Synthesis Example 6

Toluene-4-sulfonic acid 2-(3-diphenylphosphanyl-phenoxy)-ethyl ester

[0175] ##STR00016##

[0176] The same synthesis procedure as in Synthesis Example 2 was performed using compound 8 as a starting material. Separation was done by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=22:78.fwdarw.43:57) to yield a product (65% yield, white solid).

[0177] .sup.1H-NMR (600 MHz, CDCl.sub.3): 7.78 (d, J=7.8 Hz, 2H), 7.37-7.25 (m, 13H), 6.87 (t, J=7.8 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.72 (d, J=7.8 Hz, 1H), 4.34-4.29 (m, 2H), 4.06-4.03 (m, 2H), 2.42 (s, 3H);

[0178] LRMS (EI) calculated for C.sub.27H.sub.25O.sub.4PS (M.sup.+): 476.1, found: 476.1.

Synthesis Example 7

Toluene-4-sulfonic acid 3-phenylpropyl ester

[0179] ##STR00017##

[0180] A reaction vessel was charged with 3-phenyl-1-propanol (500 pL, 3.67 mmol), p-toluenesulfonylchloride (770 mg, 4.04 mmol), and pyridine (1 mL), and reaction was effected at room temperature for 1 hour. After the reaction, water and hydrochloric acid were added to the reaction system, and the product was extracted three times with ethyl acetate into the organic layer. The resulting organic layer was washed with an aqueous solution of saturated sodium bicarbonate and dried wtih MgSO.sub.4. After concentration under reduced pressure, the concentrate was purified by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=22:78.fwdarw.43:57) to yield a product (898 mg (3.09 mmol), 84% yield, colorless liquid).

[0181] .sup.1H-NMR (600 MHz, CDCl.sub.3): 7.79 (d, J=7.8 Hz, 2H), 7.34 (d, J=7.8 Hz, 2H), 7.24 (t, J=7.8 Hz, 2H), 7.17 (t, J=7.8 Hz, 1H), 7.06 (d, J=7.8 Hz, 2H), 4.03 (t, J=6.0 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 2.46 (s, 3H), 1.99-1.93 (m, 2H);

[0182] LRMS (EI) calculated for C.sub.i6H.sub.180.sub.3S (M.sup.+): 290.1, found: 290.1.

Synthesis Example 8

3-Iodopropylbenzene

[0183] ##STR00018##

[0184] A reaction vessel was charged with 3-(4-methylphenylsulfonyloxy)propylbenzene (200 mg, 0.688 mmol), sodium iodide (310 mg, 2.07 mmol), and acetone (3.4 mL), and reaction was effected at room temperature for 6 hours. After the reaction, water was added to the reaction system, and the product was extracted three times with ethyl acetate into the organic layer. The resulting organic layer was washed with saturated saline and dried with MgSO.sub.4. After concentration under reduced pressure, the concentrate was purified by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=0:100.fwdarw.11:89) to yield a product (140 mg (0.569 mmol), 83% yield, orange liquid).

[0185] .sup.1H-NMR (600 MHz, CDCl.sub.3): 7.29 (t, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 1H), 7.20 (d, J=7.8 Hz, 2H), 3.18 (t, J=7.2 Hz, 2H), 2.73 (t, J=7.2 Hz, 2H), 2.14 (quint, J=7.2 Hz, 2H);

[0186] LRMS (EI) calculated for C.sub.9H.sub.11I (M.sup.+): 246.0, found: 246.0.

[0187] As a reference specimen for use in the identification of labeled compounds, an unlabeled compound was synthesized according to the procedure described below.

Synthesis Example 9

Toluene-4-sulfonic acid 2-fluoroethyl ester

[0188] ##STR00019##

[0189] A reaction vessel was charged with 2-fluoroethanol (1.00 mL, 16.9 mmol), p-toluenesulfonylchloride (3.85 g, 20.2 mmol), N-methylmorpholine (9.30 mL, 84.5 mmol), and CH.sub.2Cl.sub.2 (50 mL), and reaction was effected at room temperature for 17 hours. After the reaction, water was added to the reaction system, and the product was extracted three times with ethyl acetate into the organic layer. The resulting organic layer was washed with saturated saline and dried with MgSO.sub.4. After concentration under reduced pressure, the concentrate was purified by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=19:81.fwdarw.40:60) to yield a product (3.79 g (17.2 mmol), >100% yield, light yellow liquid).

[0190] .sup.114-NMR (600 MHz, CDCl.sub.3): 7.81 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 4.63-4.60 (m, 1H), 4.55-4.52 (m, 1H), 4.31-4.27 (m, 1H), 4.26-4.23 (m, 1H), 2.46 (s, 3H);

[0191] LRMS (EI) calculated for C.sub.9H.sub.i1F0.sub.3S (M.sup.t): 218.0, found: 218.0.

Synthesis Example 10

[4-(2-Fluoroethoxy)phenyl]-diphenylphosphine

[0192] ##STR00020##

[0193] A reaction vessel was charged with 4-diphenylphosphanyl phenol (1.00 g, 3.59 mmol), toluene-4-sulfonic acid 2-fluoroethyl ester (1.02 g, 4.67 mmol), potassium carbonate (992 mg, 7.18 mmol), and DMF (5 mL). The reaction vessel was heated to 50 C., and reaction was effected for 1 day. After the reaction, water was added to the reaction system, and the product was extracted three times with ethyl acetate into the organic layer. The resulting organic layer was washed with saturated saline and dried with MgSO.sub.4. After concentration under reduced pressure, the concentrate was purified by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=4:96.fwdarw.25:75) to yield a product (921 mg (2.84 mmol), 80% yield, white solid).

[0194] .sup.1H-NMR (600 MHz, CDCl.sub.3): 7.69-7.43 (m, 1H), 7.36-7.24 (m, 11H), 7.01-6.89 (m, 2H), 4.75 (dt, J=48.0, 4.2 Hz, 2H), 4.21 (dt, J=28.2, 4.2 Hz, 2H);

[0195] LRMS (EI) calculated for C.sub.20H.sub.18FOP (M.sup.t): 324.1, found: 324.1.

Synthesis Example 11

Benzyl-[4-(2-fluoroethoxy)phenyl]-diphenylphosphonium bromide (TAP-001)

[0196] ##STR00021##

[0197] A reaction vessel was charged with [4-(2-fluoroethoxy)phenyl]-diphenylphosphine (100 mg, 0.308 mmol), benzyl bromide (366 L, 3.08 mmol), and MeCN (2 mL). The reaction vessel was heated to 100 C., and the contents were refluxed under heating for 45 minutes. After the reaction, the reaction solution was introduced into an open silica gel column chromatography system to elute unreacted benzyl bromide with ethyl acetate. Then, with the developing solvent being replaced by methanol:CH.sub.2Cl.sub.2=25:75, separation was done to yield a product (161 mg (0.326 mmol), 106% yield, white solid).

[0198] .sup.1H-NMR (600 MHz, CDCl.sub.3): 7.78-7.70 (m, 4H), 7.69-7.59 (m, 8H), 7.25-7.07 (m, 7H), 5.26 (d, J=14.4 Hz, 2H), 4.80 (dt, J=48.0, 4.2 Hz, 2H), 4.35 (dt, J=28.2, 4.2 Hz, 2H);

[0199] LRMS (FAB) calculated for C.sub.27H.sub.25FOP.sup.+ ([MBr].sup.+): 415.2, found: 415.2 ([MBr].sup.+).

[0200] Likewise, following the same synthesis procedure, the compounds shown below were also synthesized by reacting [4-(2-fluoroethoxy)phenyl]-diphenylphosphine with an electrophile.

TABLE-US-00001 TABLE 1 Compound Structure Yield Property MS TAP- 002 [00022] 38% White solid LRMS (FAB) calculated for C.sub.31H.sub.33FO.sub.3P.sup.+ ([MOTs].sup.+): 503.2, found: 503.2 ([MOTs].sup.+) TAP- 003 [00023] 90% Colorless solid LRMS (ESI) calculated for C.sub.29H.sub.27FO.sub.3P.sup.+ ([MBr].sup.+): 473.1, found: 473.1 ([MBr].sup.+) TAP- 004 [00024] 99% White solid LRMS (ESI) calculated for C.sub.27H.sub.24F.sub.2OP.sup.+ ([MBr].sup.+): 433.1, found: 433.1 ([MBr].sup.+) TAP- 005 [00025] 85% Colorless solid LRMS (ESI) calculated for C.sub.27H.sub.22FO.sub.4P.sup.+ ([MBr].sup.+): 469.1, found: 469.1 ([MBr].sup.+) TAP- 006 [00026] 104% (containing MeOH) White solid LRMS (ESI) calculated for C.sub.27H.sub.24ClFOP.sup.+ ([MBr].sup.+): 449.1, found: 449.1 ([MBr].sup.+) TAP- 007 [00027] 90% White solid LRMS (ESI) calculated for C.sub.28H.sub.27FO.sub.2P.sup.+ ([MCl].sup.+): 445.1, found: 445.1 ([MCl].sup.+) TAP- 008 [00028] 87% Colorless gum LRMS (ESI) calculated for C.sub.25H.sub.29FOP.sup.+ ([MOTs].sup.+): 395.1, found: 395.1 ([MOTs].sup.+) TAP- 010 [00029] 56% Colorless solid LRMS (ESI) calculated for C.sub.29H.sub.29FOP.sup.+ ([MOTs].sup.+): 443.1, found: 443.1 ([MOTs].sup.+) TAP- 011 [00030] 87% Colorless solid LRMS (ESI) calculated for C.sub.31H.sub.33FOP.sup.+ ([MBr].sup.+): 471.2, found: 471.2 ([MBr].sup.+) TAP- 012 [00031] 85% Colorless solid LRMS (ESI) calculated for C.sub.31H.sub.33FOP.sup.+ ([MBr].sup.+): 433.1, found: 433.1 ([MBr.sup.+) TAP- 013 [00032] 89% Colorless solid LRMS (ESI) calculated for C.sub.31H.sub.33FOP.sup.+ ([MBr].sup.+): 515.1, found: 515.1 ([MBr].sup.+) TAP- 014 [00033] 89% Colorless solid LRMS (ESI) calculated for C.sub.31H.sub.33FOP.sup.+ ([MBr].sup.+): 429.1, found: 429.1 ([MBr].sup.+) TAP- 015 [00034] 88% White solid LRMS (ESI) calculated for C.sub.31H.sub.33FOP.sup.+ ([MBr].sup.+): 440.1, found: 440.1 ([MBr].sup.+) TAP- 016 [00035] 77% Colorless solid LRMS (ESI) calculated for C.sub.31H.sub.33FOP.sup.+ ([MI].sup.+): 339.1, found: 339.0 ([MI].sup.+) TAP- 017 [00036] 85% Colorless solid LRMS (FAB) calculated for C.sub.23H.sub.23FOP.sup.+ ([MBr].sup.+): 365.1, found: 365.2 ([MBr].sup.+)

Synthesis Example 12

[2-(2-Fluoroethoxy)phenyl]-diphenylphosphine

[0201] ##STR00037##

[0202] The same synthesis procedure as in Synthesis Example 10 was performed using 2-diphenylphosphanyl phenol as a starting material. Separation was done by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=3:97.fwdarw.21:79) to yield a product (76% yield, white solid).

[0203] .sup.1H-NMR (600 MHz, CDCl.sub.3): 7.36-7.29 (m, 11H), 6.91-6.87 (m, 2H), 6.74-6.70 (m, 1H), 4.40 (dt, J=47.4, 4.8 Hz, 2H), 4.11 (dt, J=25.8, 4.8 Hz, 2H);

[0204] LRMS (EI) calculated for C.sub.20H.sub.18FOP (M.sup.1): 324.1, found: 324.1.

Synthesis Example 13

Benzyl-[2-(2-fluoroethoxy)phenyl]-diphenylphosphonium bromide (TAP-028)

[0205] ##STR00038##

[0206] The same synthesis procedure as in Synthesis Example 11 was performed using [2-(2-fluoroethoxy)phenyl]-diphenylphosphine as a starting material. Unreacted benzyl bromide was eluted with ethyl acetate, and then, with the developing solvent being replaced by methanol:CH.sub.2Cl.sub.2=25:75, separation was done to yield a product (70% yield, white solid).

[0207] .sup.1H-NMR (600 MHz, CDCl.sub.3): 7.90-7.83 (m, 1H), 7.80-7.73 (m, 2H), 7.66-7.58 (m, 4H), 7.55-7.46 (m, 5H), 7.35-7.25 (m, 2H), 7.23-7.16 (m, 3H), 7.01 (d, J=6.6 Hz, 1H), 5.03 (d, J=15.0 Hz, 2H), 4.51 (s, 2H), 4.48-4.46 (m, 1H), 4.44-4.42 (m, 1H);

[0208] LRMS (FAB) calculated for C.sub.27H.sub.25FOP.sup.+ ([MBr].sup.+): 415.2, found: 415.2 ([MBr].sup.+).

Synthesis Example 14

[3-(2-Fluoroethoxy)phenyl]-diphenylphosphine

[0209] ##STR00039##

[0210] The same synthesis procedure as in Synthesis Example 10 was performed using 3-diphenylphosphanyl phenol as a starting material. Separation was done by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=4:96.fwdarw.25:75) to yield a product (91% yield, white solid).

[0211] .sup.1H-NMR (600 MHz, CDCl.sub.3): 7.41-7.24 (m, 11H), 6.94-6.84 (m, 3H), 4.77-4.71 (m, 1H), 4.69-4.63 (m, 1H), 4.24-4.08 (m, 2H);

[0212] LRMS (EI) calculated for C.sub.20H.sub.18FOP (M.sup.+): 324.1, found: 324.1.

Synthesis Example 15

Benzyl-[3-(2-fluoroethoxy)phenyl]-diphenylphosphonium bromide (TAP-018)

[0213] ##STR00040##

[0214] The same synthesis procedure as in Synthesis Example 11 was performed using [3-(2-fluoroethoxy)phenyl]-diphenylphosphine as a starting material. Unreacted benzyl bromide was eluted with ethyl acetate, and then, with the developing solvent being replaced by methanol:CH.sub.2Cl.sub.2=20:80, separation was done to yield a product (88% yield, white solid).

[0215] .sup.1H-NMR (600 MHz, CDCl.sub.3): 7.80-7.74 (m, 3H), 7.70-7.64 (m, 4H), 7.63-7.58 (m, 4H), 7.50-7.46 (m, 1H), 7.35-7.31 (m, 1H), 7.24-7.20 (m, 1H), 7.16-7.09 (m, 5H), 5.49 (d, J =14.4 Hz, 2H), 4.84-4.80 (m, 1H), 4.76-4.72 (m, 1H), 4.57-4.54 (m, 1H), 4.52-4.49 (m, 1H);

[0216] LRMS (FAB) calculated for C.sub.27H.sub.25FOP.sup.+ ([MBr].sup.+): 415.2, found: 415.2 ([MBr].sup.+).

Synthesis Example 16

[3-(2-Fluoroethoxy)phenyl]-(4-methoxycarbonylphenyl)methyl-diphenylphosphonium bromide (TAP-020)

[0217] ##STR00041##

[0218] A reaction vessel was charged with [3-(2-fluoroethoxy)phenyl]-diphenylphosphine (63.8 mg, 0.197 mmol), 4-(bromomethyl)benzoic acid methyl ester (54.8 mg, 0.239 mmol), and acetonitrile (2 mL). The reaction vessel was heated to 90 C., and the contents were refluxed under heating for 4 hours. After the reaction, the reaction solution was introduced into an open silica gel column chromatography system to elute an unreacted compound with ethyl acetate. Then, with the developing solvent being replaced by methanol:CH.sub.2Cl.sub.2=20:80, separation was done to yield a product (102 mg (0.184 mmol), 93% yield, white solid).

[0219] .sup.1H-NMR (600 MHz, CDCl.sub.3): 7.85 (d, J=14.4 Hz, H), 7.79-7.74 (m, 4H), 7.70 (d, J=14.4 Hz, 2H), 7.68 (d, J=14.4 Hz, 2H), 7.63-7.58 (m, 4H), 7.46 (td, J=7.8, 4.2 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.23-7.20 (m, 2H), 7.11 (dd, J=13.2, 7.2 Hz, 1H), 5.71 (d, J=15.0 Hz, 2H), 4.77 (dt, J=47.4, 3.6 Hz, 2H), 4.54 (dt, J=28.8, 3.6 Hz, 2H), 3.86 (s, 3H);

[0220] LRMS (FAB) calculated for C.sub.29H.sub.27FO.sub.3P.sup.+ ([MBr]): 473.2, found: 473.2 ([MBr]).

Synthesis Example 17

[3-(2-Fluoroethoxy)phenyl]-(4-methoxyphenyl)methyl-diphenylphosphonium bromide (TAP-019)

[0221] ##STR00042##

[0222] A reaction vessel was charged with 4-methoxybenzylchloride (431 L, 3.19 mmol), sodium iodide (1.44 g, 9.58 mmol), and acetone (16 mL), and reaction was effected at room temperature for 18 hours. After the reaction, water was added to the reaction system, and the product was extracted three times with ethyl acetate into the organic layer. The resulting organic layer was washed with saturated saline and dried with MgSO.sub.4. After concentration under reduced pressure, the concentrate was purified by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=1:99.fwdarw.20:80) to yield 4-methoxybenzyl iodide (527 mg (2.12 mmol), 67% yield, yellow liquid).

[0223] Subsequently, the reaction vessel was charged with the resulting 4-methoxybenzyl iodide (57.3 mg, 0.231 mmol), [3-(2-fluoroethoxy)phenyl]-diphenylphosphine (50.0 mg, 0.154 mmol), and acetonitrile (2 mL). The reaction vessel was heated to 100 C., and the contents were refluxed under heating for 25 minutes. After the reaction, the reaction solution was introduced into an open silica gel column chromatography system to elute an unreacted compound with ethyl acetate. Then, with the developing solvent being replaced by methanol:CH.sub.2Cl.sub.2=10:90, separation was done to yield a product (76.3 mg (0.133 mmol), 86.6% yield, light yellow solid).

[0224] .sup.1H-NMR (600 MHz, CDCl.sub.3): 7.79 (t, J=7.2 Hz, 2H), 7.70-7.61 (m, 8H), 7.52 (td, J=8.4, 4.2 Hz, 1H), 7.46 (d, J=13.2 Hz, 1H), 7.63-7.58 (m, 4H), 7.46 (td, J=7.8, 4.2 Hz, 1H), 7.32 (d, J=9.6 Hz, 1H), 7.14 (dd, J=12.3, 7.2 Hz, 1H), 7.02 (d, J=7.2 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H), 5.22 (d, J=13.8 Hz, 2H), 4.77 (dt, J=46.5, 3.6 Hz, 2H), 4.46 (dt, J=30.0, 3.6 Hz, 2H), 3.73 (s, 3H);

[0225] LRMS (FAB) calculated for C.sub.28H.sub.27FIO.sub.2P.sup.+ ([MI].sup.+): 445.2, found: 445.2 ([MI].sup.+).

Synthesis Example 18

[3-(2-Fluoroethoxy)phenyl]-diphenyl-(3-phenylpropyl)phosphonium bromide (TAP-022)

[0226] ##STR00043##

[0227] A reaction vessel was charged with [3-(2-fluoroethoxy)phenyl]-diphenylphosphine (50.0 mg, 0.154 mmol), 3-iodopropylbenzene (76.0 mg, 0.308 mmol), and acetonitrile (1 mL). The reaction vessel was heated to 100 C., and the contents were refluxed under heating for 3.5 hours. After the reaction, the reaction solution was introduced into an open silica gel column chromatography system to elute an unreacted compound with ethyl acetate. Then, with the developing solvent being replaced by methanol:CH.sub.2Cl.sub.2=20:80, separation was done to yield a product (73.5 mg (0.145 mmol), 94% yield, light yellow solid).

[0228] .sup.1H-NMR (600 MHz, CDCl.sub.3): 7.81-7.77 (m, 2H), 7.74-7.69 (m, 4H), 7.68-7.64 (m, 4H), 7.54 (td, J=7.8, 4.2 Hz, 1H), 7.50-7.46 (m, 1H), 7.34-7.32 (m, 1H), 7.29-7.25 (m, 2H), 7.22-7.16 (m, 4H), 4.79 (dt, J=36.6, 4.2 Hz, 2H), 4.48 (dt, J=28.8, 4.2 Hz, 2H), 3.89-3.83 (m, 2H), 3.05 (t, J=7.2 Hz, 2H), 2.01-1.93 (m, 2H);

[0229] LRMS (FAB) calculated for C.sub.29H.sub.29FIOP.sup.+ ([MI].sup.+): 443.2, found: 443.2 ([MI].sup.+). Likewise, following the same synthesis procedure, the compounds shown below were synthesized by reacting [3-(2-fluoroethoxy)phenyl]-diphenylphosphine, [3-(3-fluoropropoxy)phenyl]-diphenylphosphine, or [3-(4-fluorobutoxy)phenyl]-diphenylphosphine with an electrophile.

TABLE-US-00002 TABLE 2 Compound Structure Yield Property MS TAP- 021 [00044] 92% White solid LRMS (ESI) calculated for C.sub.27H.sub.24F.sub.2OP.sup.+ ([MBr].sup.+): 433.1, found: 433.0 ([MBr].sup.+) TAP- 023 [00045] 90% Colorless solid LRMS (ESI) calculated for C.sub.27H.sub.24ClFOP.sup.+ ([MBr].sup.+): 449.1, found: 449.0 ([MBr].sup.+) TAP- 024 [00046] 55% White solid LRMS (ESI) calculated for C.sub.27H.sub.22F.sub.4OP.sup.+ ([MBr].sup.+): 469.1, found: 469.1 ([MBr].sup.+) TAP- 025 [00047] 91% White solid LRMS (FAB) calculated for C.sub.27H.sub.22F.sub.4OP.sup.+ ([MBr].sup.+): 429.1, found: 429.2 ([MBr].sup.+) TAP- 026 [00048] 97% White solid LRMS (FAB) calculated for C.sub.26H.sub.29FOP.sup.+ ([MBr].sup.+): 443.1, found: 443.2 ([MBr].sup.+) TAP- 027 [00049] 71% White solid LRMS (FAB) calculated for C.sub.21H.sub.21FOP.sup.+ ([MI].sup.+) 339.1, found: 339.2 ([MI].sup.+)

[0230] Procedure for .sup.18F-Labeling Reaction

[0231] A 12 MeV proton beam accelerated by the cyclotron Cypris HM12 (produced by Sumitomo Heavy Industries, Ltd.) was irradiated to [.sup.18O]H.sub.2O with an isotropic purity of 97% or higher (produced by Taiyo Nippon Sanso Corporation) for 40 minutes, thereby effecting an .sup.18O(p,n).sup.18F nuclear reaction to synthesize .sup.18F.sup.. Then, the solution was passed through a cation exchange resin (AG1-X8) to trap .sup.18F.sup. on the resin. The trapped .sup.18F.sup. was eluted with a 33 mM solution of K.sub.2CO.sub.3 to give an aqueous solution of [.sup.18F]KF/K.sub.2CO.sub.3. An appropriate amount of radioactivity (55-65 mCi) of the aqueous solution was taken in a volume of about 150-250 L, and added to a reaction vial containing 800 L of a Kryptfix 2.2.2. MeCN solution (20 mg/mL), and the contents were azeotropically dried under stream of helium in an oil bath at 100 C. Then, 600 L each of the prepared different MeCN solutions of labeling precursor {3 mg (6.30 mol)/600 L} was added to the reaction vial, and an .sup.18F fluorination reaction was performed at 100 C. for 10 minutes. Next, to take the second step of phosphonium compound formation, 315 mol (50 eq. relative to precursor) of the corresponding bromide (alkylating agent) was added to the vial, and a phosphonium compound formation reaction was performed at 100 C. for an appropriate time for each case. After the reaction, the vial was lifted from the oil bath, and 5 mL of water was added to the vial. The solution contained in the vial was introduced into a Sep-Pak tC18 cartridge which had been activated in advance by introducing 5 mL of ethanol and water (10 mL), and then the Sep-Pak tC18 cartridge was washed by introducing water (10 mL). After air was introduced to remove water in the cartridge, the solution containing an [.sup.18F]-labeled compound was eluted from the cartridge using ethanol (5 mL). The eluate was diluted with water (1 mL) and the resulting solution was introduced into a preparative HPLC column to effect separation and purification (preparative column: Inertsil ODS-4, 10 mm250 mm; mobile phase: PBS:MeCN=52:48; flow rate: 5.0 mL/min.; detection UV wavelength: 254 nm). The desired radioactive fraction was fractionated and diluted with pure water (20 mL). The fraction solution was introduced into a Sep-Pak tC18 cartridge which had been activated in advance by introducing ethanol (5 mL) and water (10 mL), and then the Sep-Pak tC18 cartridge was washed by introducing water (10 mL). After air was introduced to remove water in the cartridge, the [.sup.18F]-labeled compound was eluted from the cartridge into a vial using ethanol (5 mL). The eluate was azeotropically dried under stream of helium in an oil bath at 100 C. Thereafter, an appropriate amount of physiological saline was added to the reaction vial, and the resulting solution was used as a chemical solution for use in biological analysis.

[0232] The compounds of working examples as shown below were synthesized by the same procedure as mentioned above.

Example 1

Benzyl-[4-(2-[.SUP.18.F]fluoroethoxy)phenyl]-diphenylphosphonium bromide ([.SUP.18.F]TAP-001)

[0233] ##STR00050##

[0234] The total label synthesis time taken until the completion of preparing the formulation was about 1.5 hours, the radiochemical yield was 4318% (corrected for attenuation), and the radiochemical purity was at least 981.8%. FIG. 1 shows the HPLC results obtained during purification.

[0235] HPLC conditions: column: Inertsil ODS-4 (4.6x150 mm, particle size 5 m); mobile phase: MeCN/PBS=50/50; UV wavelength: 254 nm; flow rate: 1.5 mL/min.

[0236] Retention time: 4.8 min.

Example 2

Benzyl[2-(2-[.SUP.18.F]fluoroethoxy)phenyl]-diphenylphosphonium bromide ([.SUP.18.F]TAP-028)

[0237] ##STR00051##

[0238] The total label synthesis time taken until the completion of preparing the formulation was about 1.5 hours, the radiochemical yield was 129.9% (corrected for attenuation), and the radiochemical purity was at least 925.8%.

[0239] HPLC conditions: column: InertSustain C-18 (4.6x150 mm, particle size 5 m); mobile phase: MeCN/PBS=50/50; UV wavelength: 254 nm; flow rate: 1.5 mL/min.

[0240] Retention time: 4.4 min.

Example 3

Benzyl[3-(2-[.SUP.18.F]fluoroethoxy)phenyl]-diphenylphosphonium bromide ([.SUP.18.F]TAP-003)

[0241] ##STR00052##

[0242] The total label synthesis time taken until the completion of preparing the formulation was about 1.5 hours, the radiochemical yield was 368.4% (corrected for attenuation), and the radiochemical purity was at least 990.1%.

[0243] HPLC conditions: column: InertSustain C-18 (4.6150 mm, particle size 5 m); mobile phase: MeCN/PBS=50/50; UV wavelength: 254 nm; flow rate: 1.5 mL/min.

[0244] Retention time: 4.4 min.

Example 4

[3-(2-[.SUP.18.F]fluoroethoxy)phenyl]-(4-methoxycarbonylphenyl)methyl-diphenylphosphonium bromide ([.SUP.18.F]TAP-020)

[0245] ##STR00053##

[0246] In the process of the synthesis of the labeled compound [.sup.18F]TAP-004, 4-(bromomethyl)benzoic acid methyl ester used as a reagent for phosphonium compound formation is solid; therefore, after the first step of fluorination reaction, acetonitrile was once distilled away and then a solution of the reagent in acetonitrile (72 mg (50 eq.)/600 L) was added again, and thereafter the second reaction step was performed. The other synthesis operations were done by the same procedure as the aforementioned procedure for .sup.18F-labeling reaction. The total label synthesis time taken until the completion of preparing the formulation was about 1.5 hours, the radiochemical yield was 32% (corrected for attenuation), and the radiochemical purity was at least 95%.

[0247] HPLC conditions: column: InertSustain C-18 (4.6150 mm, particle size 5 m); mobile phase: MeCN/PBS=50/50; UV wavelength: 254 nm; flow rate: 1.0 mL/min.

[0248] Retention time: 5.5 min.

Example 5

[3-(2- [.SUP.18.F]fluoroethoxy)phenyl]-(4-methoxyphenyl)methyl-diphenylphosphonium bromide ([.SUP.18.F]TAP-019)

[0249] ##STR00054##

[0250] The synthesis operations were performed by the same procedure as the aforementioned procedure for .sup.18F-labeling reaction, except that (4-methoxyphenyl)methylchloride was used as an alkylating agent and the reaction temperature was set to 130 C. The total label synthesis time taken until the completion of preparing the formulation was about 1.5 hours, the radiochemical yield was 42% (corrected for attenuation), and the radiochemical purity was at least 99%.

[0251] HPLC conditions: column: InertSustain C-18 (4.6150 mm, particle size 5 m); mobile phase: MeCN/PBS=50/50; UV wavelength: 254 nm; flow rate: 1.0 mL/min.

[0252] Retention time: 6.8 min.

Example 6

[.SUP.18.F][3-(2-fluoroethoxy)phenyl]-(3-phenylpropyl)-diphenylphosphonium bromide ([18F]TAP-022)

[0253] ##STR00055##

[0254] In the process of the synthesis of the labeled compound [.sup.18F]TAP-006, 3-iodopropylbenzene was used as an alkylating agent. Since 3-iodopropylbenzene is solid, after the first step of fluorination reaction, acetonitrile was once distilled away and then a solution of the reagent in acetonitrile (78 mg (50 eq.)/600 L) was added again, and thereafter the second reaction step was performed. The other synthesis operations were done by the same procedure as the aforementioned procedure for .sup.18F-labeling reaction. The total label synthesis time taken until the completion of preparing the formulation was about 1.5 hours, the radiochemical yield was 21% (corrected for attenuation), and the radiochemical purity was at least 99%.

[0255] HPLC conditions: column: InertSustain C-18 (4.6150 mm, particle size 5 m); mobile phase: MeCN/PBS=50/50; UV wavelength: 254 nm; flow rate: 1.5 mL/min.

[0256] Retention time: 6.8 min.

[0257] Likewise, the compounds shown below were also synthesized according to the same synthesis procedure.

TABLE-US-00003 TABLE 3 Radiochemical yield (%)/ Structural Electro- HPLC retention time Compound formula phile (HPLC conditions) [.sup.18F]TAP- 002 [00056] [00057] 12% 5.8 min. (column: Inertsil ODS-4 (4.6 150 mm, particle size: 5 m); mobile phase: MeCN/PBS = 50/50, UV wavelength: 254 nm; flow rate: 1.5 mL/min.) [.sup.18F]TAP- 004 [00058] [00059] 49% 6.1 min. (column: Inertsil ODS-4 (4.6 150 mm, particle size: 5 m); mobile phase: MeCN/PBS = 50/50; UV wavelength: 254 nm; flow rate: 1.5 mL/min.) [.sup.18F]TAP- 008 [00060] [00061] 22% 4.9 min. (column: InertSustain C-18 (4.6 150 mm, particle size: 5 m); mobile phase: MeCN/PBS = 50/50; UV wavelength: 254 nm; flow rate: 1.5 mL/min.) [.sup.18F]TAP- 024 [00062] [00063] 31% 5.2 min. (column: InertSustain C-18 (4.6 150 mm, particle size: 5 m); mobile phase: MeCN/PBS = 50/50; UV wavelength: 254 nm; flow rate: 1.5 mL/min.)

Example 16

Analysis of Phosphonium Compound Formation Reaction Time

[0258] The reaction according to the scheme shown below was performed by following the aforementioned procedure for .sup.18F-labeling reaction. In this process, the reaction was performed using varied times of phosphonium compound formation reaction, whereby the resulting radiochemical yields for the different cases were compared. The results are shown in the table given below. Among the cases where the reaction time at the second step was set to 20, 10 or 5 min., the highest radiochemical yield was obtained for the case of setting the reaction time to 5 min.

##STR00064##

TABLE-US-00004 Reaction time at Radiochemical 2nd step (X) yield (%) 20 min (n = 4) 36 8.4 10 min (n = 3) 39 9.3 5 min (n = 13) 47 7.4

Test Example 1

Mouse PET/CT Imaging

[0259] The animals used in this measurement were 6-10-week-old male Slc:ICR mice (from Japan SLC, Inc.). Each of different physiological saline solutions of the [.sup.18F]-labeled compounds (200 L, 1.94-14.7 MBq) used in this measurement was administered via the caudal vein to the awake mice, and the mice were left to settle for 50 minutes. Then, the mice were fixed under isoflurane anesthesia (2%, 1.5 mL/min.), and after 60 minutes of the administration, the whole bodies of the mice were imaged by small-animal PET (ClairvivoPET produced by Shimadzu Corporation) for 10 minutes. Subsequently, while the mice were kept fixed, their whole bodies were imaged by small-animal CT (ClairvivoCT produced by Shimadzu Corporation). The PET data were reconstructed by 3D-DRAMA, and the pixel values of the obtained PET images were converted to SUV to generate SUV images. These images were fused with CT images to produce fused images. The results are shown in FIG. 2.

[0260] The accumulation of radioactivity in the myocardium was observed in all the cases of using [.sup.18F]TAP-001, 018, 019, and 022 this confirmed that these compounds are usable for myocardial imaging. In particular, high-contrast myocardial images were obtained in the cases of using [.sup.18F]TAP-018, 019, and 022.

Test Example 2

Mouse Biodistribution Study

[0261] The animals used in this measurement were 6-8-week-old male Slc:ICR mice (from Japan SLC, Inc.) (n=4). Each of different physiological saline solutions of the [.sup.18F]-labeled compounds (200 L, 370-740 kBq) used in this measurement was administered to the awake mice via the caudal vein, and after 60 or 120 minutes of the administration, the mice were euthanized by cervical dislocation under isoflurane anesthesia. After blood was sampled from the heart immediately, the heart, lung, liver, spleen, kidney, small intestine, thigh muscle, thigh bone, and brain were excised and measured for amount of radioactivity by a counter. The weights of the excised organs were measured, and on that basis, the accumulation rates per gram of the organs with respect to dose (% dose/g of organ, % ID/g) were calculated as indicators for accumulation of the chemical compounds used (n=4). The results are shown in FIG. 3.

[0262] The accumulation of labeled compound in the myocardium was observed in all the cases of using [.sup.18F]TAP-001, 018, 019, and 022 this confirmed that the radioactivity more highly accumulates in the myocardium than in other adjacent organs. In particular, the ratio of radioactivity accumulations in the myocardium and liver (heart/liver ratio)those accumulations were considered most likely to affect imagingwas calculated and found to be 2.70 for [.sup.18F]TAP-001, 9.40 for [.sup.18F]TAP-018, 4.56 for [.sup.18F]TAP-019, or 4.98 for [.sup.18F]TAP-022, at the time point of 60 minutes. This demonstrated that all the compounds accumulate in a heart-specific manner.

Test Example 3

Rat Biodistribution Study

[0263] The biodistribution study of [.sup.18F]TAP-018 in rats was conducted by the same procedure as in Test Example 2 using 6-week-old male Wistar rats (from Japan SLC, Inc.) (n=4). The results are summarized in a bar graph (FIG. 4). [.sup.18F]TAP-018 highly accumulated in the heart, and the heart/liver ratio was found to be about 15.5 at the time point of 60 minutes. This value is about ten times higher than the value of 1.5 for [.sup.18F]FBnTP which has been used as a gold standard, and is sufficiently higher than the value of 9.2 for [.sup.18F]FTPP which is currently under clinical study. This demonstrates that [.sup.18F]TAP-018 is useful as a myocardial perfusion imaging agent.

Test Example 4

Small-Animal PET Study in Rats

[0264] The myocardial imaging study of [.sup.18F]TAP-018 in rats was conducted using 6-week-old male Wistar rats. 200 L (7.83-9.66 MBq) of a physiological saline solution of the test compound [.sup.18F]TAP-018 was administered via the caudal vein to the rats fixed under isoflurane anesthesia (2%, 1.5 mL/min.), and then the whole bodies of the rats were imaged by small-animal PET at time points from 0 to 120 minutes after the administration. Subsequently, while the rats were kept fixed, their whole bodies were imaged by small-animal CT. The PET data were reconstructed by 3D-DRAMA, and the pixel values of the obtained PET images were converted to SUV to generate SUV images. These images were fused with CT images to produce fused images. Further, the locations of the myocardium, lung and liver were identified based on the fused images, and regions of interest (ROI) were drawn to calculate respective SUVavg values. FIG. 5A shows the PET images taken until 60 minutes after the administration. FIG. 5B shows the radioactivity-time curves in the heart, liver and lung. As evident, radioactivity disappeared rapidly from the liver until 10 minutes after the administration, whereas a high level of radioactivity accumulated in the heart immediately after the administration. These results of PET imaging demonstrated that [.sup.18F]TAP-018 is useful as a myocardial perfusion agent.