Radiosynthesis and Radiotracer Properties of a 7-(2-[F-18]Fluoroethoxy)-6-methoxy-pyrrolidinylquinazoline for Imaging of Phosphodiesterase 10A with PET

Phosphodiesterase 10A (PDE10A) is a key enzyme of intracellular signal transduction which is involved in the regulation of neurotransmission. The molecular imaging of PDE10A by PET is expected to allow a better understanding of physiological and pathological processes related to PDE10A expression and function in brain. The aim of this study was to develop a new 18F-labeled PDE10A ligand based on a 6,7-dimethoxy-4-pyrrolidinylquinazoline and to evaluate its properties in biodistribution studies. Nucleophilic substitution of the 7-tosyloxy-analogue led to the 7-[18F]fluoroethoxy-derivative [18F]IV with high PDE10A affinity (KD,PDE10A=14 nM), radiochemical yields of 25±9% (n=9), high radiochemical purity of ≥99% and specific activities of 110-1100 GBq/mol. [18F]IV entered rapidly into the brain of female CD-1 mice with a peak uptake of 2.3%ID/g in striatum at 5 min p.i.. High metabolic stability in brain was observed. However, blocking studies revealed no target specific accumulation of [18F]IV. Therefore, successful imaging of PDE10A using 18F-labeled 6,7-dialkoxyquinazoline derivatives requires further structural optimization.