Kuo-Shyan Lin
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Prostate-specific membrane antigen (PSMA) is a transmembrane protein with an extracellular catalytic site that hydrolyzes N-acetylaspartate glutamate. It is associated with many solid cancers, and most notably prostate cancer as per its namesake. Moreover, PSMA expression correlates with prostate specific antigen expression and Gleason score which means the detected PSMA expression can be utilized to diagnose and stage prostate cancer patients. PSMA expression also has prognostic and predicative values which can further inform prostate cancer management and precision medicine. Its large extracellular domain makes it an ideal drug target for antibody and small molecule development. Antibodies are larger and have longer blood residence time and are expensive to develop, while small molecules have faster clearance and penetrance making them the ideal vector for further uses. Many lysine-urea-glutamate-based PSMA inhibitors targeting the folate enzymatic site such as [¹⁸F]DCFPyL and [⁹⁹ᵐTc]Tc- EDDA/HYNIC-iPSMA have been developed and evaluated in clinical and pre-clinical settings. However, a common problem for glutamate-based tracers is their high non-specific kidney and salivary gland uptake which can be problematic in detecting metastatic lesions and can cause side-effects like xerostomia when translating imaging-based radiopharmaceuticals into therapeutic ones.Hence, there remains a need to further optimize and increase the specificity and affinity of PSMA-targeting radiopharmaceuticals. We present a peptide-chemistry based synthesis of novel PSMA-targeting radiopharmaceuticals which is further evaluated for their in vitro and in vivo characterization based on parameters including binding affinity, hydrophilicity, labelling yield and purity, stability, biodistribution and tracer uptake, and tumour-to-background ratio inLNCaP cell and tumour xenograft models. Here, we report several successful candidates labelled with technetium-99m and fluorine-18 for SPECT and PET imaging, respectively, with ideal pharmacodynamic and pharmacokinetic properties for further pre-clinical evaluation.
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