AUTHOR=Zeng Fanxing , Nye Jonathon A. , Voll Ronald J. , Mun Jiyoung , Goodman Mark M. 

TITLE=Synthesis and Evaluation of [11C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT2C Receptors

JOURNAL=Frontiers in Neuroscience

VOLUME=15

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.766320

DOI=10.3389/fnins.2021.766320

ISSN=1662-453X

ABSTRACT=<p>The serotonin 5-HT<sub>2</sub><sub><italic>C</italic></sub> receptor (5-HT<sub>2</sub><sub><italic>C</italic></sub>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 <italic>in vivo</italic> imaging and quantification of 5-HT<sub>2</sub><sub><italic>C</italic></sub>R densities represents a significant technological advancement in understanding both the normal function and pathophysiology of the 5-HT<sub>2</sub><sub><italic>C</italic></sub>R. Four 7-halogen-2-phenyl isoindolones (7-F, Cl, Br, I) were synthesized and displayed high affinities for 5-HT<sub>2</sub><sub><italic>C</italic></sub>R and high selectivity over 5-HT<sub>2</sub><sub><italic>A</italic></sub> and 5-HT<sub>2</sub><sub><italic>B</italic></sub>. [<sup>11</sup>C]7-Chloro-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (<bold>6</bold>) and [<sup>11</sup>C]7-iodo-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (<bold>9</bold>) were synthesized in high radiochemical yield of 37–44% [<italic>n</italic> = 10, decay corrected from end of (<sup>11</sup>C)CH<sub>3</sub>I synthesis] with high radiochemical purity <italic>via O</italic>-methylation with [<sup>11</sup>C]CH<sub>3</sub>I, respectively. MicroPET imaging studies in male rats with or without 5-HT<sub>2</sub><sub><italic>C</italic></sub> antagonist SB-242084 showed that [<sup>11</sup>C]<bold>6</bold> and [<sup>11</sup>C]<bold>9</bold> display specific bindings to 5-HT<sub>2</sub><sub><italic>C</italic></sub>R in the choroid plexus and hippocampus. <italic>In vivo</italic> microPET brain imaging studies in rhesus monkeys demonstrated that [<sup>11</sup>C]<bold>6</bold> and [<sup>11</sup>C]<bold>9</bold> 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 [<sup>11</sup>C]<bold>6</bold>, and 3.7 and 2.7, respectively, for [<sup>11</sup>C]<bold>9</bold>, which were reduced by administration of a dose of SB-242084. Our results support the candidacy of [<sup>11</sup>C]<bold>6</bold> and [<sup>11</sup>C]<bold>9</bold> for further study as radioligands for <italic>in vivo</italic> quantitation of 5-HT<sub>2</sub><sub><italic>C</italic></sub> sites by PET.</p>