PET-examination and metabolite evaluation in monkey of [11C]NAD-299, a radioligand for visualisation of the 5-HT1A receptor

NAD-299 is a selective 5-HT1A receptor antagonist that is currently developed as a putative antidepressant drug. [C-11]NAD-299 was examined in the cynomolgus monkey brain with positron emission tomography (PET). After radioligand injection high accumulation of radioactivity was observed in the frontal and temporal cortex and the raphe nuclei, regions known to contain a high density of 5-HT1A receptors. Peak equilibrium appeared already at about 10 ruin after i.v. injection. Pre-treatment with a high dose of the antagonist WAY-100635 reduced the amount of radioactivity in the cortex and the raphe to the level of the cerebellum. A strong pre-treatment effect could also be achieved using pindolol, a partial agonist at the 5-HT1A-receptors. The appearance of labeled metabolites in monkey plasma was measured with HPLC. At 45 minutes after injection 49% (range 27-55%, n = 5) of radioactivity in monkey plasma represented unchanged radioligand. [C-11]NAD-299 was metabolized to more polar labeled metabolites of which one has the same chromatographic mobility as the descyclobutyl analogue of NAD-299 (NAD-272). The results indicate that [C-11]NAD-299 has potential as a PET radioligand for studies of 5-HT1A receptors in the primate brain. (C) 2002 Elsevier Science Inc. All rights reserved.