Cocaine congeners as PET imaging probes for dopamine terminals.
The PET imaging properties of three phenyltropane drugs with differing affinities and selectivities for the dopamine over serotonin transporter, were compared.


METHODS
Carbon-11-CFT (WIN 35,428, 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane), 11C-CCT (RTI-131, 2 beta-carbomethoxy-3 beta-(4-monochlorophenyl)tropane), and 11C-CDCT (dichloropane, 2 beta-carbomethoxy-3 beta-(3,4-dichlorophenyl)tropane) were evaluated as imaging probes for dopamine neurons in five normal and in two MPTP-treated cynomolgus monkeys (macaca fascicularis) using a high-resolution PET imaging system (PCR-I).


RESULTS
For 11C-CFT, the specific binding ratio (as defined by the ratio of radioactivity levels in striatum versus cerebellum) was 4.2 +/- 0.8 in caudate and 4.9 +/- 1.2 in putamen at 60 min and 4.9 +/- 1.2 and 5.5 +/- 1.1 at 90 min in control animals. In MPTP-treated monkeys the corresponding ratios were 1.4 +/- 0.1 in caudate and 1.5 +/- 0.1 in putamen at 60 min and 1.3 +/- 0.1 in caudate and 1.4 +/- 0.3 in putamen at 90 min. For the monochloro analog of CFT, 11C-CCT, the ratios in control caudate and putamen were 2.7 +/- 0.4 and 3.4 +/- 0.3, respectively, at 60 min and 3.7 +/- 0.5 and 4.4 +/- 0.6, respectively, at 90 min. In MPTP-treated animals, corresponding ratios were 1.4 +/- 0.4 and 1.5 +/- 0.3 at 60 min and 1.4 +/- 0.4 and 1.6 +/- 0.4 at 90 min. The dichloro analog of CFT, CDCT, which has the highest affinity for the dopamine transporter, generated the lowest ratios in control brains, 2.3 +/- 0.4 in caudate and 2.4 +/- 0.5 in putamen at 60 min. In one MPTP-treated monkey, the corresponding ratios were 1.6 +/- 0.4 and 1.8 +/- 0.3. In comparison with 11C-CFT, both 11C-CCT and 11C-CDCT were less selective and had high uptake in the thalamus.


CONCLUSIONS
The present results clearly indicate that 11C-CFT is a useful ligand for monitoring dopamine neuronal degeneration.
Brownell
A L
AL
Department of Radiology, Massachusetts General Hospital, Boston 02114, USA.
Elmaleh
D R
DR
Meltzer
P C
PC
Shoup
T M
TM
Brownell
G L
GL
Fischman
A J
AJ
Madras
B K
BK
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes; D003042:Cocaine / Q000031:analogs & derivatives; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D009411:Nerve Endings / Q000737:chemistry* / Q000000981:diagnostic imaging; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000000981:diagnostic imaging*; D014055:Tomography, Emission-Computed
D002250:Carbon Radioisotopes; D018765:Dopamine Uptake Inhibitors; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D003042:Cocaine; D004298:Dopamine