In vitro assessment of the agonist properties of the novel 5-HT1A receptor ligand, CUMI-101 (MMP), in rat brain tissue

Introduction: Development of agonist positron emission tomography (PET) radioligands for the 5-HT neurotransmitter system is an important target to enable the understanding of human 5-HT function in vivo. [C-11]CUMI-101, proposed as the first 5-HT1A receptor agonist PET ligand, has been reported to behave as a potent 5-HT1A agonist in a cellular system stably expressing human recombinant 5-HT1A receptors. In this study, we investigate the agonist properties of CUMI-101 in rat brain tissue. Methods: [S-35]-GTP gamma S binding studies were used to determine receptor function in HEK (human embryonic kidney) 293 cells transfected with human recombinant 5-HT1A receptors and in rat cortex and rat hippocampal tissue, following administration of CUMI-101 and standard 5-HT1A antagonists (5-HT, 5-CT and 8-OH-DPAT). Results: CUMI-101 behaved as an agonist at human recombinant 5-HT1A receptors (pEC(50) 9.2). However, CUMI-101 did not show agonist activity in either rat cortex or hippocampus at concentrations up to 10 mu M. In these tissues, CUMI-behaved as an antagonist with pK(B)s of 9.2 and 9.3, respectively. Conclusions: Our studies demonstrate that as opposed to its behavior in human recombinant system, in rat brain tissue CUMI-101 behaves as a potent 5-HT1A receptor antagonist. (C) 2011 Elsevier Inc. All rights reserved.