P-[F-18]-MPPF - A POTENTIAL RADIOLIGAND FOR PET STUDIES OF 5-HT1A RECEPTORS IN HUMANS

The purpose of this study was to develop a radiopharmaceutical that co uld be used to selectively image 5-HT1A receptors with positron emissi on tomography (PET). No-carrier-added pyridinyl)-p-[F-18]fluorobenzami do]ethylpiperazine (p-[F-18]-MPPF, 2) was synthesized by the nucleophi lic substitution of the corresponding nitro precursor 1 with K[F-18]/K ryptofix 2.2.2. in dimethyl sulfoxide (DMSO) at 140 degrees C for 20 m in followed by purification with high-performance liquid chromatograph y (HPLC) in 10% yield in a synthesis time of 90 min from end of bombar dment (EOB). Specific activity was 1-4 Ci/mu M. Biodistribution studie s in rats showed that the initial uptake of 2 in the brain was high (0 .7% dose/g tissue at 2 min). It was then rapidly eliminated. Rates of elimination were significantly slower in brain regions with high conce ntrations of 5-HT1A receptors (hippocampus, cortex, and hypothalamus) than in control regions. The maximum hippocampal/cerebellar ratio was 5.6:1 at 30 min postinjection. Uptake values in serotonergic, but not in control, regions were significantly reduced by prior treatment with either (+/-)-8-OH-DPAT (2 mg/kg, i.v., 5 min priori or WAY 100635 (1 mg/kg, i.v., 5 min prior). Radioactivity in the femur did not increase with time, suggesting that in vivo defluorination may not be the majo r route of metabolism. PET studies of 2 in a monkey demonstrated selec tive uptake and retention of 2 in the hippocampus. The hippocampal/cer ebellar ratio was 3:1 at 30 min postinjection. The ratio was reduced t o I:1 by administering (+/-)-8-OH-DPAT (2 mg/kg, i.v.) 23 min postinje ction of 2. Analyses of arterial plasma by HPLC revealed that 20% of r adioactivity in the plasma remained as the parent compound 2 at 30 min postinjection. The results suggest that p-[F-18]-MPPF may be a useful radioligand for studying cerebral 5-HT1A receptors in humans with PET techniques. (C) 1997 Wiley-Liss, Inc.