Synthesis and preclinical evaluation of an 18F labeled PDE7 inhibitor for PET neuroimaging.

INTRODUCTION: Phosphodiesterase 7 (PDE7) hydrolyzes selectively cyclic adenosine monophosphate (cAMP) which is an intracellular second messenger. PDE7 is expressed by 2 genes which are both present in the brain. To date there is no radiotracer for PDE7 imaging described and detection of PDE7 has only been performed by ex vivo techniques. In this report we describe the radiosynthesis of a novel fluorine-18 labeled radiotracer for PDE7 as well as the in vivo evaluation in mice to verify whether it has potential for imaging of PDE7 in the brain.

METHODS: We have synthesized a potent fluorinated PDE7 inhibitor, [(18)F]MICA-003 (PDE7 IC(50)=17 nM) and the corresponding tosylate precursor for radiolabeling. [(18)F]MICA-003 was injected in C57BL/6J mice (n=5) and in vivo images were acquired by μPET imaging. Radiometabolite analysis in plasma and brain was performed to determine the stability of the radioligand.

RESULTS: [(18)F]MICA-003 was synthesized by direct fluorination of the tosylate and produced in high decay corrected radiochemical yield (40%), high radiochemical purity (>98%) and high specific activity (86-497 GBq/μmol). μPET imaging revealed that [(18)F]MICA-003 crosses the blood brain barrier and has a homogenous distribution over the brain which washes out after the initial peak uptake. [(18)F]MICA-003 was quickly metabolized in plasma with 8.9%±0.59% of intact [(18)F]MICA-003 remaining at 5m in post injection. We observed the formation of three distinct radiometabolites of which the main radiometabolite was also detected in the brain in a proportion of 25.7±2.57% at this same time point.

CONCLUSION: We have described the synthesis and in vivo evaluation of a novel radioligand for PDE7 imaging. Despite high uptake in the brain and favorable kinetics in vivo, the presence of a brain penetrant radiometabolite makes [(18)F]MICA-003 unfavorable for the accurate quantification of PDE7 and more stable spiroquinazolinones analogs are in development.