title: Radiochemical synthesis and tissue distribution of p-[18F]DMPPF, a new 5-HT1A ligand for PET, in rats.
abstract: Several studies have demonstrated the potential of p-[(18)F]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-DMPPNO(2), MEM-p-MPPF and MEM-p-MPPNO(2) were isolated and fully identified ((1)H and (13)C NMR, LC-MS). The final compound, p-[(18)F]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/mumol. 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-[(18)F]DMPPF was of the same order of magnitude as that of p-[(18)F]MPPF. The amount of radioactivity reaching the brain was much higher (approximately fivefold at 60 min) for p-[(18)F]DMPPF compared with p-[(18)F]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-[(18)F]DMPPF appears to be less metabolized than p-[(18)F]MPPF. p-[(18)F]DMPPF deserves further evaluation as a radiopharmaceutical candidate.
authors.affiliation: Cyclotron Research Center, Liege University, Sart Tilman B.30, B-4000 Liege, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Defraiteur
authors.forename: Christian
authors.initials: C
authors.lastname: Lemaire
authors.forename: André
authors.initials: A
authors.lastname: Luxen
authors.forename: Alain
authors.initials: A
authors.lastname: Plenevaux
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D007553:Isotope Labeling; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D011869:Radioligand Assay / Q000379:methods; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C513932:4-(2'-hydroxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-fluorobenzamido)ethyl)piperazine; D001549:Benzamides; D010879:Piperazines; D019275:Radiopharmaceuticals; D044282:Receptor, Serotonin, 5-HT1A