A 7-(2-[F-18]Fluoroethoxy)-6-Methoxy-Pyrrodinylquinazoline for PET Imaging of PDE10A: Radiosynthesis and Evaluation in vivo and in vitro

Pharmacological treatment of the enzymatic activity of phosphodiesterase 10A (PDE10A) is a potential approach in the therapy of several neuropsychiatric disorders such as schizophrenia and psychoses. For improved treatment1 and diagnosis2 thereof, the development of potent and selective brain penetrable PDE10A inhibitors is forced. Based on a 6,7-dimethoxy-4-pyrrolidinylquinazoline (Ki = 4 nM1) we developed a 7-[18F]fluoroethoxy-derivative [18F]V as a potential PET radiotracer for imaging PDE10A in brain. Its non-radioactive analogue V showed strongest PDE10A inhibition (Ki = 53 nM) and selectivity in enzyme activity studies and was chosen for radiolabelling, initially performed via two-step-reaction. Therefore the conversion of 1,3-bistosyloxyethane I into [18F]fluoroethyltosylate II, using the [18F]KF-K2.2.2-carbonate complex, was followed by direct etherification of deprotonated 7-hydroxy-derivative III to afford [18F]V (3.5-4.5 h, based on [18F]F- aqueous solution; RCY 18-29%, radiochemical purities 92-99%). Next, an improved one-step radiosynthesis was developed by direct substitution of the 7-tosyloxy-analogue IV with n.c.a. [18F]fluoride (3-4 h, RCY 17-40%, radiochemical purity ≥ 99%, specific activities 110-1110 GBq/µmol). Purification of [18F]V was performed by SPE and semi-preparative HPLC with sample monitoring by radio-TLC and -HPLC. In vitro homologous competition assays on PDE10A transfected SF21 cells showed a high PDE10A affinity of [18F]V (KD = 14 nM). By HPLC as well as shake-flask methods a moderate lipophilicity of [18F]V was determined (logD7.0-7.4 ~ 2.6). In vivo biodistribution studies of [18F]V in female CD-1 mice revealed a high initial brain uptake of 2.3%ID/g at 5 min p.i. in striatum. Nevertheless, the baseline uptake of [18F]V in striatum(1.14%ID/g 60 min p.i.) was not inhibited by blocking with V (1.3%ID/g) as well as highly PDE10A specific inhibitor MP-10 (1.4%ID/g). Screening of metabolism in vivo showed, that ~ 70% and 96% of the radioactivity corresponded to native radioligand in plasma and brain at 30 and 60 min p.i., respectively, and no defluorination of the radioligand was observed. Finally, despite promising in vitro outcome and convenient radiosynthesis, results obtained in vivo show necessity of structural optimization of [18F]V to make it suitable for neuroimaging of PDE10A with PET.