Phosphodiesterase (PDE) is a family of enzymes that deactivate intracellular second messengers, cAMP and cGMP, which regulate a wide variety of biological processes. Impaired cAMP and/or cGMP regulations upon overexpression of PDEs been described in various types of cancers. Inhibition of PDE to restore the functions of cAMP and/or cGMP is promising as a molecule-specific targeted therapy approach. Recently, it is reported that phosphodiesterase 10A (PDE10A) is elevated in human colon tumor cell lines and clinical specimens, and that highly specific PDE10A inhibitors selectively inhibit colon tumor cell growth. Imaging of tumorous PDE10A by positron emission tomography (PET) would substantially facilitate the development of PDE10A inhibitors and also enables us to monitor the treatment effects of the inhibitors on tumor growth. Numerous PET tracers have been developed for the successful imaging of PDE10 in the brain. Among these ligands, [18F]TZ20A, potent (IC50 = 0.26 nM) and selective (&gt;1,000 times over other PDEs), was selected to be synthesized and evaluated with mice bearing colon tumors. However, our studies showed the liver clearance of [18F]TZ20A was too fast from the blood, leading to insufficient delivery of [18F]TZ20A to tumor. Thus, we labeled and evaluated novel ligands that circulated longer in the blood stream. [11C]MCI-030 and [11C]MCI048 are potent and PDE10A selective ligands that derived from the scaffold of sulindac, a nonsteroid anti-inflammatory drug (NSAID). [11C]MCI-030 and [11C]MCI048 were labeled via O-methylation with [11C]MeOTf using an automated synthesis module. High chemistry (&gt; 90%) and radiochemistry purity (&gt; 95%) was achieved. The uptakes of the tracers were evaluated with HT-29 and HCT-116 cells (colorectal cancer cells) and intestinal epithelial cells (IEC). HT-29 and HCT-116 cells were also implanted to immunodeficient mice for in vivo evaluation of the tracers. The tumor bearing mice were intravenously injected with tracers, euthanized at 5, 30 and 60 min post injection, and dissected. The organ distributions (ID%/g) of tracers were calculated. Radioactive metabolites in mice plasma were assayed by HPLC. Mice PET imaging studies were also performed. We reported the successful automated radiosynthesis of fluorine-18 and carbon-11 radiotracers, and promising results from the in vitro and in vivo evaluation of the tracers for PET Imaging of PDE10 in colorectal tumors.

Radiosynthesis and evaluation of fluorine-18 and carbon-11 radiotracers for PET Imaging of PDE10A in colorectal cancer

255th National Meeting (2018)

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