Synthesis, pharmacology and preclinical evaluation of 11 C-labeled 1,3-dihydro-2H-benzo[d]imidazole-2-ones for imaging γ8-dependent transmembrane AMPA receptor regulatory protein

European Journal of Medicinal Chemistry
Zhen ChenSteven H Liang

Abstract

a-Amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are implicated in the pathology of neurological diseases such as epilepsy and schizophrenia. As pan antagonists for this target are often accompanied with undesired effects at high doses, one of the recent drug discovery approaches has shifted to subtype-selective AMPA receptor (AMPAR) antagonists, specifically, via modulating transmembrane AMPAR regulatory proteins (TARPs). The quantification of AMPARs by positron emission tomography (PET) would help obtain insights into disease conditions in the living brain and advance the translational development of AMPAR antagonists. Herein we report the design, synthesis and preclinical evaluation of a series of TARP γ-8 antagonists, amenable for radiolabeling, for the development of subtype-selective AMPAR PET imaging agents. Based on the pharmacology evaluation, molecular docking studies and physiochemical properties, we have identified several promising lead compounds 3, 17-19 and 21 for in vivo PET studies. All candidate compounds were labeled with [11C]COCl2 in high radiochemical yields (13-31% RCY) and high molar activities (35-196 GBq/μmol). While tracers 30 ([11C]17) &32 ([11C]21) crossed the blood-brain barri...Continue Reading

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