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Novel [Ga/Lu]Ga/Lu-AZ-093 as PSMA-Targeting Agent for Diagnosis and Radiotherapy. | LitMetric

AI Article Synopsis

Article Abstract

Prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer cells can serve as a target for imaging and radioligand therapy (RLT). Previously, [Ga]Ga-P16-093, containing a Ga(III) chelator, ,'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-,'-diacetic acid (HBED-CC), displayed excellent PSMA-targeting properties and showed a high tumor uptake and retention useful for diagnosis in prostate cancer patients. Recently, [Lu]Lu-PSMA-617 has been approved by the U.S. food and drug administration (FDA) for the treatment of prostate cancer patients. Derivatives of PSMA-093 using AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid), as the chelator, were designed as alternative agents forming complexes with both diagnostic and therapeutic radiometals, such as gallium-68 (log = 22.18) or lutetium-177 (log = 21.85). The aim of this study is to evaluate AAZTA-Gly--(methylcarboxy)-Tyr-Phe-Lys-NH-CO-NH-Glu (designated as AZ-093, ) leading to a gallium-68/lutetium-177 theranostic pair as potential PSMA targeting agents. Synthesis of the desired precursor, AZ-093, , was effectively accomplished. Labeling with either [Ga]GaCl or [Lu]LuCl in a sodium acetate buffer solution (pH 4-5) at 50 °C in 5 to 15 min produced either [Ga]Ga- or [Lu]Lu- with high yields and excellent radiochemical purities. Results of binding studies, cell uptake, and retention (using PSMA-positive prostate carcinoma cells line, 22Rv1-FOLH1-oe) were comparable to that of [Ga]Ga-P16-093 and [Lu]Lu-PSMA-617, respectively. Specific cellular uptake was determined with or without the competitive blocking agent (2 μM of "cold" PSMA-11). Cellular binding and internalization showed a time-dependent increase over 2 h at 37 °C in the PSMA-positive cells. The cell uptakes were completely blocked by the "cold" PSMA-11 suggesting that they are competing for the same PSMA binding sites. In the mouse model with implanted PSMA-positive tumor cells, both [Ga]Ga- and [Lu]Lu- displayed excellent uptake and retention in the tumor. Results indicate that [Ga]Ga/[Lu]Lu- (Ga]Ga/[Lu]Lu-AZ-093) is potentially useful as PSMA-targeting agent for both diagnosis and radiotherapy of prostate cancer.

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Source
http://dx.doi.org/10.1021/acs.molpharmaceut.4c00020DOI Listing

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