Synthesis and biodistribution of (R,S)-[O-methyl-11C]-1-[3-(5-methoxy-1,2,3,4-tetrahydro-1-naphtalenyl)propyl]-4-phenylpiperazine (PNU-157760), a putative radioligand for 5-HT1A receptors

Racemic 1-[3-(5-methoxy-1,2,3,4-tetrahydro-1-naphtalenyl)propyl]-4-phenylpiperazine (PNU-157760) was labeled with carbon-11 (t(1/2) = 20.4 min) as a putative radioligand for the noninvasive assessment of 5-HT1A receptors in vivo with positron emission tomography (PET). The radiochemical synthesis consisted of O-methylation of desmethyl precursor with [C-11]methyl iodide in the presence of potassium tert-butoxide in DMF. The desmethyl precursor for the radiosynthesis of [C-11]PNU-157760, was prepared by a convenient one-step demethylation of PNU-157760 with boron tribromide. (R,S)-[O-Methyl-C-11]-1-[3-(5-methoxy-1,2,3,4-tetrahydro-1-naphtalenyl)propyl] with >99% radiochemical purity was obtained in 30 min with a radiochemical yield of 10 +/- 5% (EOS, nondecay corrected) and a specific radioactivity of 2.5 +/- 1 Ci/mu mol. Biodistribution studies in rats showed that [C-11]PNU-157760 readily crosses the blood-brain barrier with a maximum of brain uptake at 30 min after injection; however, the low specific-to-nonspecific binding ratio in vivo as evidenced by the low hippocampus/cerebellum uptake ratio (1.17 at 60 min postinjection) does not make [C-11]PNU-157760 a promising radioligand for serotonin 5-HT1A receptors. (C) 1998 Academic Press