New halogenated [C-11]WAY analogues, [C-11]6FPWAY and [C-11]6BPWAY - Radiosynthesis and assessment as radioligands for the study of brain 5-HT1A receptors in living monkey

[Carbonyl-C-11]WAY-100635 ([C-11]WAY) is an established radioligand for the study of brain serotonin(1A) (5-HT1A) receptors in living animals and huma ns with positron emission tomography (PET). There is a recognised need to d evelop halogenated ligands for 5-HT1A receptors, either for labelling with longer lived fluorine-18 for more widespread application with PET or with i odine-123 for application with single photon emission tomography (SPET). He re we used autoradiography and PET to assess two new halogenated anlogues o f WAY, namely 6BPWAY and 6FPWAY [N-(2-(1-(4-(2-methoxyphenyl)-piperazinyl) ethyl))-N-(2-(6-bromo-/fluoro-pyridinyl))cyclohexanecarboxamide] as prospec tive radioligands, initially using carbon-11 as the radiolabel. Labelling o f 6BPWAY and 6FPWAY with carbon-11 was accomplished by acylation of the cor responding secondary amine precursors with [carbonyl-C-11]cyclohexanecarbon yl chloride. After incubation of human brain crysections with [C-11]6BPWAY or [C-11]6FPWAY, the highest accumulation of radioactivity was observed in cortical areas and the hippocampal formation. Both radioligands had high no nspecific binding. There was a rapid accumulation of radioactivity in the m onkey brain after intravenous injection of [C-11]6BPWAY and [C-11]6FPWAY. H igh accumulation of radioactivity was observed in the frontal and temporal cortex and the raphe nuclei, areas known to contain a high density of 5-HT1 A receptors. The ratios of radioactivity in receptor-rich temporal cortex t o that in receptor poor cerebellum at peak equilibrium were 1.9 (at 10 min) and 3.0 at (at 20 min) for [C-11]6BPWAY and [C-11]6FPWAY, respectively. In pretreatment experiments with high doses of unlabelled WAY, the level of r adioactivity in the frontal and temporal cortex and the raphe nuclei was re duced to the same level as in the cerebellum. Radioactive metabolites of [C -11]6FPWAY appeared at a rate similar to those for [C-11]WAY, with 17% of t he radioactivity in plasma represented by unchanged radioligand after 40 mi n. Radioactive metabolites of [C-11]6BPWAY appeared much more slowly. At 40 min after injection 45% of the radioactivity in plasma still represented u nchanged radioligand. The results indicate that 6-pyridinyl radiohalogented analogues of WAY are new leads to radioligands for PET or SPET. (C) 2001 E lsevier Science Inc. All rights reserved.