Synthesis and evaluation of [ 11C]FR194921 as a nonxanthine-type PET tracer for adenosine A 1 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(2 H)-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]CH 3I 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 μmol −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 A 1 receptor antagonist, which indicated specific binding of the radioligand to adenosine A 1 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 A 1 receptors in vivo by positron emission tomography (PET).