High-resolution imaging of brain 5-HT1B receptors in the rhesus monkey using [11C]P943

The serotonin 5-HT1B receptors regulate the release of serotonin and are involved in various disease states, including depression and schizophrenia. The goal of the study was to evaluate a high affinity and high selectivity antagonist, [C-11]P943, as a positron emission tomography (PET) tracer for imaging the 5-HT1B receptor. [C-11]P943 was synthesized via N-methylation of the precursor with [C-11]methyl iodide or [C-11]methyl triflate using automated modules. The average radiochemical yield was approx. 10% with radiochemical purity of >99% and specific activity of 8.8 +/- 3.6 mCi/nmol at the end-of-synthesis (n=37). PET imaging was performed in non-human primates with a high-resolution research tomograph scanner with a bolus/infusion paradigm. Binding potential (BPND) was calculated using the equilibrium ratios of regions to cerebellum. The tracer uptake was highest in the globus pallidus and occipital cortex, moderate in basal ganglia and thalamus, and lowest in the cerebellum, which is consistent with the known brain distribution of 5-HT1B receptors. Infusion of tracer at different specific activities (by adding various amount of unlabeled P943) reduced BPND values in a dose-dependent manner, demonstrating the saturability of the tracer binding. Blocking studies with GR127935 (2 mg/kg iv), a selective 5-HT1B/5-HT1D antagonist, resulted in reduction of BPND values by 42-95% across regions; for an example, in occipital region from 0.71 to 0.03, indicating a complete blockade. These results demonstrate the saturability and specificity of [C-11]P943 for 5-HT1B receptors, suggesting its suitability as a PET radiotracer for in vivo evaluations of the 5-HT1B receptor system in humans. Published by Elsevier Inc.