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. [(11)C]CUMI-101, proposed as the first 5-HT(1A) receptor agonist PET ligand, has been reported to behave as a potent 5-HT(1A) agonist in a cellular system stably expressing human recombinant 5-HT(1A) receptors. In this study, we investigate the agonist properties of CUMI-101 in rat brain tissue.
Methods: [(35)S]-GTPγS binding studies were used to determine receptor function in HEK (human embryonic kidney) 293 cells transfected with human recombinant 5-HT(1A) 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-HT(1A) receptors (pEC(50) 9.2). However, CUMI-101 did not show agonist activity in either rat cortex or hippocampus at concentrations up to 10 μM. 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-HT(1A) receptor antagonist.
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