Synthesis and Evaluation of [C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for Imaging of 5-HT Receptors.

The serotonin 5-HT receptor (5-HT 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 imaging and quantification of 5-HT R densities represents a significant technological advancement in understanding both the normal function and pathophysiology of the 5-HT R. Four 7-halogen-2-phenyl isoindolones (7-F, Cl, Br, I) were synthesized and displayed high affinities for 5-HT R and high selectivity over 5-HT and 5-HT . [C]7-Chloro-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one () and [C]7-iodo-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one () were synthesized in high radiochemical yield of 37-44% [ = 10, decay corrected from end of (C)CHI synthesis] with high radiochemical purity -methylation with [C]CHI, respectively. MicroPET imaging studies in male rats with or without 5-HT antagonist SB-242084 showed that [C] and [C] display specific bindings to 5-HT R in the choroid plexus and hippocampus. microPET brain imaging studies in rhesus monkeys demonstrated that [C] and [C] 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 [C], and 3.7 and 2.7, respectively, for [C], which were reduced by administration of a dose of SB-242084. Our results support the candidacy of [C] and [C] for further study as radioligands for quantitation of 5-HT sites by PET.