Radiosynthesis and preclinical evaluation of a carbon-11 labeled PDE7 inhibitor for PET neuroimaging

Xiao, Z.; Sun, J.; Fujinaga, M.; Wei, H.; Zhao, C.; Haider, A.; Van, R.; Yamasaki, T.; Zhang, Y.; Rong, J.; Hu, K.; Chen, J.; Leon, E. C.; Hiraishi, A.; Wei, J.; Xu, Y.; Shao, Y.; Zhang, H.-T.; Lloyd, K. C. K.; Wang, L.; Zhang, M.-R.; Liang, S. H.

doi:10.1101/2021.06.12.447900

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bioRxiv · 10.1101/2021.06.12.447900

Radiosynthesis and preclinical evaluation of a carbon-11 labeled PDE7 inhibitor for PET neuroimaging

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Abstract

BackgroundDysfunction of cyclic nucleotide phosphodiesterase 7 (PDE7) has been associated with excess intracellular cAMP concentrations, fueling pathogenic processes that are implicated in neurodegenerative disorders. The aim of this study was to develop a suitable PDE7-targeted positron emission tomography (PET) probe that allows non-invasive mapping of PDE7 in the mammalian brain. MethodsBased on a spiro cyclohexane-1,4-quinazolinone scaffold with known inhibitory properties towards PDE7, we designed and synthesized a methoxy analog that was suitable for carbon-11 labeling. Radiosynthesis was conducted with the respective desmethyl precursor using [11C]MeI. The resulting PET probe, codenamed [11C]26, was evaluated by cell uptake studies, ex vivo biodistribution and radiometabolite studies, as well as in vivo PET experiments in rodents and nonhuman primates (NHP). ResultsTarget compound 26 and the corresponding phenolic precursor were synthesized in 2-3 steps with overall yields of 49.5% and 12.4%, respectively. An inhibitory constant (IC50) of 31 nM towards PDE7 was obtained and no significant interaction with other PDE isoforms were observed. [11C]26 was synthesized in high molar activities (170 - 220 GBq/{micro}mol) with radiochemical yields of 34{+/-}7%. In vitro cell uptake of [11C]26 was 6-7 folds higher in PDE7 overexpressing cells, as compared to the controls, whereas an in vitro specificity of up to 90% was measured. Ex vivo metabolite studies revealed a high fraction of intact parent in the rat brain (98% at 5 min and 75% at 30 min post injection). Considerable brain penetration was further corroborated by ex vivo biodistribution and PET imaging studies - the latter showing heterogenic brain uptake. While marginal specific binding was observed by PET studies in rodents, a moderate, but dose-dependent, blockade was observed in the NHP brain following pretreatment with non-radioactive 26. ConclusionIn this work, we report on the preclinical evaluation of [11C]26 (codename [11C]P7-2104), a PDE7-targeted PET ligand that is based on a spiroquinazolinone scaffold. [11C]26 displayed promising in vitro performance characteristics, a moderate degree of specific binding in PET studies with NHP. Accordingly, [11C]26 will serve as a valuable lead compound for the development of a new arsenal of PDE7-targeted probes with potentially improved in vivo specificity.

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Xiao, Z., Sun, J., Fujinaga, M., Wei, H., Zhao, C., Haider, A., Van, R., Yamasaki, T., Zhang, Y., Rong, J., Hu, K., Chen, J., Leon, E. C., Hiraishi, A., Wei, J., Xu, Y., Shao, Y., Zhang, H.-T., Lloyd, K. C. K., Wang, L., Zhang, M.-R., Liang, S. H.. 2021-06-13. Radiosynthesis and preclinical evaluation of a carbon-11 labeled PDE7 inhibitor for PET neuroimaging. https://doi.org/10.1101/2021.06.12.447900

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