title: Synthesis and evaluation of [11C]FR194921 as a nonxanthine-type PET tracer for adenosine A1 receptors in the brain.
abstract: This report describes the synthesis of [11C]2-(1-methyl-4-piperidinyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone ([11C]FR194921), a highly selective, nonxanthine-type adenosine A(1) receptor antagonist, used in brain imaging in rats and conscious monkeys as a potential novel PET tracer. [11C]FR194921 was successfully synthesized in 19 min after [11C]CH3I formation. The radiochemical yield was 38+/-3%; and radioactivity was 4.1+/-0.4 GBq, calculated from end of synthesis; radiochemical purity was higher than 99%; and the specific radioactivity was 25.0+/-8.1 GBq micromol(-1) (n=5). In a rat experiment, the distribution of [11C]FR194921 was higher in the hippocampus, striatum and cerebellum regions. This accumulation was significantly decreased by approximately 50% by pretreatment with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1 receptor antagonist, which indicated specific binding of the radioligand to adenosine A1 receptors. In conscious monkey PET experiments, [11C]FR194921 accumulated in several regions of the brain, especially in the occipital cortex, thalamus and striatum. These results suggest that [11C]FR194921 can be used as an agent for imaging adenosine A1 receptors in vivo by positron emission tomography (PET).
authors.affiliation: Basic Research Division, The Medical and Pharmacological Research Center Foundation, Ishikawa 925-0613, Japan. matsuya@mprcf.or.jp
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsuya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamatsu
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Murakami
authors.forename: Akihiro
authors.initials: A
authors.lastname: Noda
authors.forename: Rikiya
authors.initials: R
authors.lastname: Ichise
authors.forename: Yuji
authors.initials: Y
authors.lastname: Awaga
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nishimura
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D011724:Pyridazines / Q000737:chemistry / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013194:Staining and Labeling / Q000379:methods; D014018:Tissue Distribution; D051598:Whole Body Imaging / Q000379:methods; D019820:Xanthine / Q000493:pharmacokinetics
chemical_list: C497088:2-(1-methyl-4-piperidinyl)-6-(2-phenylpyrazolo(1,5-a)pyridin-3-yl)-3(2H)-pyridazinone; D058916:Adenosine A1 Receptor Antagonists; D002250:Carbon Radioisotopes; D010880:Piperidines; D011724:Pyridazines; D019275:Radiopharmaceuticals; D043682:Receptor, Adenosine A1; D019820:Xanthine