Synthesis and Evaluation of [(11)C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT(2)(C) Receptors

The serotonin 5-HT(2)(C) receptor (5-HT(2)(C)R) is abundantly expressed throughout the central nervous system, and involved in a variety of neuroendocrine and neurobehavioral processes. The development of a selective radioligand that will enable in vivo imaging and quantification of 5-HT(2)(C)R densities represents a significant technological advancement in understanding both the normal function and pathophysiology of the 5-HT(2)(C)R. Four 7-halogen-2-phenyl isoindolones (7-F, Cl, Br, I) were synthesized and displayed high affinities for 5-HT(2)(C)R and high selectivity over 5-HT(2)(A) and 5-HT(2)(B). [(11)C]7-Chloro-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (6) and [(11)C]7-iodo-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (9) were synthesized in high radiochemical yield of 37–44% [n = 10, decay corrected from end of ((11)C)CH(3)I synthesis] with high radiochemical purity via O-methylation with [(11)C]CH(3)I, respectively. MicroPET imaging studies in male rats with or without 5-HT(2)(C) antagonist SB-242084 showed that [(11)C]6 and [(11)C]9 display specific bindings to 5-HT(2)(C)R in the choroid plexus and hippocampus. In vivo microPET brain imaging studies in rhesus monkeys demonstrated that [(11)C]6 and [(11)C]9 exhibit excellent blood-brain barrier penetration. The contrast of bindings to the choroid plexus and hippocampus compared to the cerebellum peaked at 2.7 and 1.6, respectively, for [(11)C]6, and 3.7 and 2.7, respectively, for [(11)C]9, which were reduced by administration of a dose of SB-242084. Our results support the candidacy of [(11)C]6 and [(11)C]9 for further study as radioligands for in vivo quantitation of 5-HT(2)(C) sites by PET.