2-carbomethoxy-8-(3-fluoropropyl)-3-(4-iodophenyl)tropane and vanoxerine

The recently developed radioligand [123I]FP-CIT is suitable for clinical single-photon emission tomography (SPET) imaging of the dopamine (DA) transporter in vivo. To date it has remained unclear whether dopaminergic medication influences the striatal [123I]FP-CIT binding. The purpose of this study was to investigate the influence of this medication on [123I]FP-CIT binding in the brain. We used an animal model in which we administered dopaminomimetics, antipsychotics and an antidepressant. In vivo [123I]FP-CIT binding to the DA and serotonin transporters was evaluated after subchronic and acute administration of the drugs. The administered medication induced small changes in striatal [123I]FP-CIT binding which were not statistically significant. As expected, the DA reuptake blocker GBR 12,909 induced a significant decrease in [123I]FP-CIT binding. [123I]FP-CIT binding in the serotonin-rich hypothalamus was decreased only after acute administration of fluvoxamine. The results of this study suggest that dopaminergic medication will not affect the results of DA transporter SPET imaging with [123I]FP-CIT.

Topics: Animals; Brain; Cerebellum; Corpus Striatum; Dopamine Agonists; Dopamine Antagonists; Dopamine Uptake Inhibitors; Hypothalamus; Iodine Radioisotopes; Male; Piperazines; Rats; Rats, Wistar; Tropanes

Iodine-123 labelled 2beta-carbomethoxy-3beta-4-iodophenylnortropane (nor-beta-CIT), a radioiodinated cocaine analogue, was evaluated as an agent for the in vivo labelling of serotonin transporters by biodistribution studies in rats. Intravenous injection of [123I]nor-beta-CIT resulted in high accumulation of radioactivity in brain areas with high densities of serotonin (hypothalamus) and dopamine transporters (striatum), although the binding was less pronounced in the hypothalamus. While binding of [123I]nor-beta-CIT in the hypothalamus was blocked significantly by fluvoxamine (a selective serotonin transporter blocker) but not by GBR12,909 (a selective dopamine transporter blocker), the opposite was observed in the striatum. The results of this study indicate that [123I]nor-beta-CIT, although not being a selective radioligand, binds specifically to serotonin transporters in the hypothalamus in vivo and thus suggest that [123I]nor-beta-CIT promises to be a suitable radioligand for single-photon emission tomography imaging of serotonin transporters in humans.

Topics: Animals; Brain; Carrier Proteins; Cocaine; Dopamine Uptake Inhibitors; Fluvoxamine; Iodine Radioisotopes; Male; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Piperazines; Radionuclide Imaging; Rats; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Plasma Membrane Transport Proteins; Tropanes

beta-CIT-FP [N-(3-fluoropropyl)-2 beta-carbomethoxy-3 beta-(4-iodophenyl)nortropane] is a cocaine analogue with high affinity for the dopamine transporter. Positron emission tomography (PET) studies with [O-methyl-11C] beta-CIT-FP ([11C] beta-CIT-FP) has shown that equilibrium conditions were approached but, however, not reached at the end of measurement. Moreover, metabolite studies of [11C] beta-CIT-FP in monkey plasma demonstrated a lipophilic-labelled metabolite that may enter the brain. We therefore labelled beta-CIT-FP with fluorine-18 in a position that may avoid the formation of labelled lipophilic metabolites. The more long-lived radionuclide (18F) was used to allow for measurements over longer time. [N-fluoropropyl- 18F] beta-CIT-FP ([18F] beta-CIT-FP) was prepared by N-alkylation of nor-beta-CIT with [18F]fluoropropyl bromide. PET studies were performed in cynomolgus monkeys. [18F] beta-CIT-FP entered the brain rapidly. There was a high concentration of radioactivity in the striatum and much lower in the thalamus, neocortex, and cerebellum. The striatum-to-cerebellum ratio was about 5 at time of transient equilibrium, which occurred after 60 to 100 min. After pretreatment with GBR 12909, radioactivity in the striatum was markedly reduced, thus indicating specific [18F] beta-CIT-FP binding to the dopamine transporter. The fraction of unchanged [18F] beta-CIT-FP determined by HPLC was 10-15% after 140 min. No lipophilic labelled metabolites were detected. The absence of measurable lipophilic labelled metabolites and the occurrence of transient equilibrium within the time of the PET measurement indicate that [18F] beta-CIT-FP is superior to [11C] beta-CIT-FP as a PET radioligand for quantification of the dopamine transporter in the human brain.

Topics: Animals; Brain; Brain Chemistry; Carbon Radioisotopes; Carrier Proteins; Chromatography, High Pressure Liquid; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Fluorine Radioisotopes; Macaca fascicularis; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Piperazines; Tomography, Emission-Computed; Tropanes