p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

✍ Scribed by Chyng-Yann Shiue; Grace G. Shiue; P. David Mozley; Mei-Ping Kung; Zhi-Ping Zhuang; Hee-Joung Kim; Hank F. Kung

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 154 KB
• Volume: 25
• Category: Article
• ISSN: 0887-4476
• DOI: 10.1002/(sici)1098-2396(199702)25:2<147::aid-syn5>3.0.co;2-c

✦ Synopsis

The purpose of this study was to develop a radiopharmaceutical that could be used to selectively image 5-HT 1A receptors with positron emission tomography (PET). No-carrier-added 4-(28-methoxyphenyl)-1-[28-(N-29-pyridinyl)-p-[ 18 F]fluorobenzamido]ethylpiperazine ( p-[ 18 F]-MPPF, 2) was synthesized by the nucleophilic substitution of the corresponding nitro precursor 1 with K[ 18 F]/Kryptofix 2.2.2. in dimethyl sulfoxide (DMSO) at 140°C for 20 min followed by purification with high-performance liquid chromatography (HPLC) in 10% yield in a synthesis time of 90 min from end of bombardment (EOB). Specific activity was 1-4 Ci/µM.

Biodistribution studies 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 concentrations of 5-HT 1A 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 (6)-8-OH-DPAT (2 mg/kg, i.v., 5 min prior) 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 major route of metabolism. PET studies of 2 in a monkey demonstrated selective uptake and retention of 2 in the hippocampus. The hippocampal/ cerebellar ratio was 3:1 at 30 min postinjection. The ratio was reduced to 1:1 by administering (6)-8-OH-DPAT (2 mg/kg, i.v.) 23 min postinjection of 2. Analyses of arterial plasma by HPLC revealed that 20% of radioactivity in the plasma remained as the parent compound 2 at 30 min postinjection. The results suggest that p-[ 18 F]-MPPF may be a useful radioligand for studying cerebral 5-HT 1A receptors in humans with PET techniques.