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内容記述 |
Introduction: Phosphodiesterases (PDEs) are enzymes responsible for hydrolyzing cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), key second messengers involved in various cellular processes. Among the 11 PDE sub-families, phosphodiesterase 1 (PDE1) has been widely implicated in the central and peripheral pathologies. Despite its importance, there is still no suitable radioligand for clinically imaging PDE1 with positron emission tomography currently. Herein, we report [11C]PF-04822163 as a novel potential radioligand candidate for imaging the PDE1 receptor with PET.Methods: The synthesis of phenolic 11C-labeling precursor 10 is outlined in Figure 1A. Starting from compound 1, nitration with fuming nitric acid gave compound 2 in 73% yield. Then oxidation reaction with KMnO4 converted the aldehyde group to the carboxylic acid group and the Pd-mediated reduction reaction with H2 converted the nitro group to the amino group, and the following cyclization reaction afforded compound 5 in 17% yield over three steps. The acetylation of 5 with Ac2O and chlorination of compound 6 with Vilsmeier reagent provided key intermediate 7 in 47% yield over two steps. Nucleophilic substitution of methyl 6-chloro-2,3-dihydro-1H-indene-1-carboxylate with compound 7 and the subsequent hydrolysis and decarboxylation afforded compound 9 as a racemic precursor in 61% yield over three steps. Finally, chiral precursor 10 was obtained through HPLC chiral separation of 9 in 47% yield. The radiosynthesis of [11C]PF-04822163 was achieved via the 11C-methylation of precursor 10 with [11C]MeI in the presence of NaOH as the base in dimethylformamide at 30 oC for 5 minutes (Figure 1B). The in vitro autoradiography study was performed on sagittal rat brain sections with [11C]PF-04822163 (Figure 1C). Dynamic PET imaging was carried out on SD rats and pretreatment with PF-04822163 (1 mg/kg) was performed 10 min before the tracer administration in the blocking study.Results: The phenolic precursor 10 of [11C]PF-04822163 was obtained in 1.6% yield over nine steps (Figure 1A). Ligand [11C]PF-04822163 was obtained in 25 ± 10% yields (decay-corrected) with high molar activities of 106-194 GBq/µmol (2.9-5.2 Ci/μmol) (Figure 1B). In the autoradiography study, ligand [11C]PF-04822163 exhibited high radioactivity accumulation in the striatum and substantia nigra (Figure 1C). In the blocking study, the radioactivity level in PDE1B-rich regions remarkably decreased with the pretreatment with PF-04822163 (Figure 1C). In PET imaging on rats, [11C]PF-04822163 rapidly crossed the blood-brain barrier (BBB) with high uptake in the striatum (SUV3 min = 2), followed by an evident washout. Pretreatment with PF-04822163 gave a marginal uptake decrease in various brain regions during blocking conditions.Conclusions: We have described a facile synthetic route to the phenolic 11C-labeling precursor 10. The radiosynthesis of [11C]PF-04822163 was obtained in favorable radiochemical yields and high molar activities. The preliminary evaluation, including in vitro autoradiography and PET imaging studies, demonstrated that [11C]PF-04822163 had promising characteristics as a potential PET ligand candidate for imaging PDE1. Further medicinal chemistry efforts are necessary to improve the specific binding in vivo. |
