Fluorine-18-labeled tropane analogs for PET imaging studies of the dopamine transporter.

A series of PET imaging studies were conducted with two fluorine-18-labeled tropane analoges, [(18)F](+)-FTT and [(18)F](+)-FCT. Both compounds possessed a high affinity and selectivity for the dopamine transporter and had a higher accumulation in the basal ganglia, a brain region having a high density of the dopamine transporter (DAT) than the cerebellum, a reference region devoid of dopaminergic terminals. [(18)F](+)-FCT had a higher brain uptake and more suitable basal ganglia:cerebellum (BG:Cb) ratio than [(18)F](+)-FTT. [(18)F](+)-FCT also displayed reversible binding kinetics in vivo, indicating that the measurement of DAT density in vivo with PET will be relatively insensitive to changes in cerebral blood flow that can occur as a consequence of disease or prolonged cocaine abuse. The uptake of [(18)F](+)-FCT was also displaced by an intravenous injection of cocaine (1.0 mg/kg), which is consistent with the labeling of the DAT in vivo by this radiotracer. These data suggest that [(18)F](+)-FCT may be a suitable radiotracer for studying DAT function in vivo with PET.

Self-administration of cocaine analogs by rats.

RATIONALE: A novel scheme for the synthesis of cocaine analogs from vinylcarbenoid precursors has made available compounds that have a diverse range of affinities for the DA and 5-HT transporters. These compounds were used to explore the relationship between their biochemical properties and their reinforcing effects. OBJECTIVES: The objective was to assess the reinforcing efficacy of selected cocaine analogs and compare the results with their selectivity in binding to DA and 5-HT transporters. METHODS: Rats were prepared with chronically indwelling intravenous cannulae and trained to self-administer cocaine on a progressive ratio (PR) schedule. A range of doses of seven cocaine analogs were substituted for cocaine in separate groups of animals. RESULTS: The results demonstrate a wide range of reinforcing efficacies and potencies among the seven selected drugs. Four tropane analogs (WF-11, WF-23, WF-24, WF-55) were found to support self-administration behavior on a PR schedule while three did not (WF-31, WF-54 and WF-60). The DA/5-HT selectivity ratio was found to be a better predictor of self-administration behavior than affinity at the DA transporter alone. CONCLUSION: These data suggest that drugs with a higher affinity for the DA versus the 5-HT transporter are more likely to be self-administered.