Radiochemical synthesis and tissue distribution of p-[F-18]DMPPF, a new 5-HT1A ligand for PET, in rats

Several studies have demonstrated the potential of p-[F-18]MPPF as a radiophanilaceutical to study the 5-HT1A receptor family in animals and humans. A structural modification leading to a higher radioactive signal at an equipotent dose would greatly enhance this potential. With this goal, the desmethylated 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-fluorobenzamidolethyl]-piperazine (p-MPPF), identified as p-DMPPF, was synthesized, labeled with fluorine-18 and evaluated through ex vivo tissue distribution in rats. The new compounds p-DMPPF, p-DMPPNO2, MEM-p-MPPF and MEM-p-MPPNO2 were isolated and fully identified (H-1 and C-13 NMR, LC-MS). The final compound, p-[F-18]DMPPF, was obtained ready for injection, with an overall radiochemical yield of 10% (EOB corrected) within 90 min and a specific activity of 62 GBq/mu mol. Tissue distributions showed that the carbon-fluorine bond was stable in vivo and that this compound could cross the blood-brain barrier. For kidney, lung, heart, spleen, bone, testicle, liver and muscle, the percentage of injected dose per gram of tissue obtained with p-[F-18]DMPPF was of the same order of magnitude as that of p-[F-18]MPPF. The amount of radioactivity reaching the brain was much higher (approximately fivefold at 60 min) for p-[F-18]DMPPF compared with p-[F-18]MPPF, which was taken as reference. The distribution and specificity were in total agreement with the known localization of 5-HT1A receptors in rats. The radioactivity increase was more important for specific tissues (hippocampus and frontal cortex) than for cerebellum or striatum, leading to better contrast (hippocampus/cerebellum=5.8 at 60 min). The levels of metabolites found in plasma showed that p-[F-18]DMPPF appears to be less metabolized than p-[F-18]MPPF. p-[F-18]DMPPF deserves further evaluation as a radiopharmaceutical candidate. (c) 2006 Elsevier Inc. All rights reserved.