Radiosynthesis and Evaluation of 11C-CIMBI-5 as a 5-HT2A Receptor Agonist Radioligand for PET

PET brain imaging of the serotonin 2A (5-hydroxytryptamine 2A, or 5-HT2A) receptor has been widely used in clinical studies, and currently, several well-validated radiolabeled antagonist tracers are used for in vivo imaging of the cerebral 5-HT2A receptor. Access to 5-HT2A receptor agonist PET tracers would, however, enable imaging of the active, high-affinity state of receptors, which may provide a more meaningful assessment of membrane-bound receptors. In this study, we radiolabel the high-affinity 5-HT2A receptor agonist 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-[11C-OCH3]methoxybenzyl)ethanamine (11C-CIMBI-5) and investigate its potential as a PET tracer. Methods: The in vitro binding and activation at 5-HT2A receptors by CIMBI-5 was measured with binding and phosphoinositide hydrolysis assays. Ex vivo brain distribution of 11C-CIMBI-5 was investigated in rats, and PET with 11C-CIMBI-5 was conducted in pigs. Results: In vitro assays showed that CIMBI-5 was a high-affinity agonist at the 5-HT2A receptor. After intravenous injections of 11C-CIMBI-5, ex vivo rat studies showed a specific binding ratio of 0.77 ± 0.07 in the frontal cortex, which was reduced to cerebellar levels after ketanserin treatment, thus indicating that 11C-CIMBI-5 binds selectively to the 5-HT2A receptor in the rat brain. The PET studies showed that the binding pattern of 11C-CIMBI-5 in the pig brain was in accordance with the expected 5-HT2A receptor distribution. 11C-CIMBI-5 gave rise to a cortical binding potential of 0.46 ± 0.12, and the target-to-background ratio was similar to that of the widely used 5-HT2A receptor antagonist PET tracer 18F-altanserin. Ketanserin treatment reduced the cortical binding potentials to cerebellar levels, indicating that in vivo 11C-CIMBI-5 binds selectively to the 5-HT2A receptor in the pig brain. Conclusion: 11C-CIMBI-5 showed a cortex-to-cerebellum binding ratio equal to the widely used 5-HT2A antagonist PET tracer 18F-altanserin, indicating that 11C-CIMBI-5 has a sufficient target-to-background ratio for future clinical use and is displaceable by ketanserin in both rats and pigs. Thus, 11C-CIMBI-5 is a promising tool for investigation of 5-HT2A agonist binding in the living human brain.

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