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

Defraiteur, Caroline; Lemaire, Christian; Luxen, André; Plenevaux, Alain

doi:10.1016/j.nucmedbio.2006.03.010

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 5 , Pages 667-675, July 2006

Radiochemical synthesis and tissue distribution of p-[¹⁸F]DMPPF, a new 5-HT_1A ligand for PET, in rats

Cyclotron Research Center, Liege University, Sart Tilman B.30, B-4000 Liege, Belgium

Received 3 March 2006; received in revised form 16 March 2006; accepted 31 March 2006. published online 15 June 2006.

Abstract

Several studies have demonstrated the potential of p-[¹⁸F]MPPF as a radiopharmaceutical to study the 5-HT_1A 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-fluorobenzamido]ethyl]-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 (¹H and ¹³C NMR, LC–MS). The final compound, p-[¹⁸F]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/μmol. 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-[¹⁸F]DMPPF was of the same order of magnitude as that of p-[¹⁸F]MPPF. The amount of radioactivity reaching the brain was much higher (approximately fivefold at 60 min) for p-[¹⁸F]DMPPF compared with p-[¹⁸F]MPPF, which was taken as reference. The distribution and specificity were in total agreement with the known localization of 5-HT_1A 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-[¹⁸F]DMPPF appears to be less metabolized than p-[¹⁸F]MPPF. p-[¹⁸F]DMPPF deserves further evaluation as a radiopharmaceutical candidate.