MMP is a 5-HT1A receptor antagonist in rat brain membranes

Objectives Several radiotracers have been used to probe central 5-HT1A receptors clinically, however, the most successful to date are antagonists which label both high and low affinity receptor states. To further enhance the understanding of the role of 5-HT and / or 5-HT1A receptors in CNS disorders, an agonist radiotracer would be an invaluable tool. The aim of this study was to pharmacologically characterize the putative 5-HT1A receptor agonist PET ligand, MMP [2-(4-(4-(2-methoxyphenyl) piperazin-1-yl)butyl)-4-methyl-1, 2, 4-triazine-3, 5(2H, 4H)diaone], in rat brain tissue.

Methods The agonist activity of MMP was assessed in rat cortical and hippocampal membranes using the [35S]-GTPγS binding technique. Membranes were incubated with MMP and [35S]-GTPγS, after which the reaction was terminated and bound [35S]-GTPγS levels were determined by liquid scintillation spectrometry.

Results MMP (up to 10 μM) did not stimulate [35S]-GTPγS binding in either rat cortical or hippocampal membranes. In addition, MMP inhibited [35S]-GTPγS binding stimulated by 5-HT (at EC80), yielding an estimated pKB of 9.2.

Conclusions These data suggest that MMP acts as a potent 5-HT1A receptor antagonist in rat native tissue