Novel [68Ga/177Lu]Ga/Lu-AZ-093 as PSMA-Targeting Agent for Diagnosis and Radiotherapy

Prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer cells can serve as a target for imaging and radioligand therapy (RLT). Previously, [Ga-68]Ga-P16-093, containing a Ga(III) chelator, N,N '-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N '-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-177]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 K = 22.18) or lutetium-177 (log K = 21.85). The aim of this study is to evaluate AAZTA-Gly-O-(methylcarboxy)-Tyr-Phe-Lys-NH-CO-NH-Glu (designated as AZ-093, 1) leading to a gallium-68/lutetium-177 theranostic pair as potential PSMA targeting agents. Synthesis of the desired precursor, AZ-093, 1, was effectively accomplished. Labeling with either [Ga-68]GaCl3 or [Lu-177]LuCl3 in a sodium acetate buffer solution (pH 4-5) at 50 degrees C in 5 to 15 min produced either [Ga-68]Ga-1 or [Lu-177]Lu-1 with high yields and excellent radiochemical purities. Results of in vitro binding studies, cell uptake, and retention (using PSMA-positive prostate carcinoma cells line, 22Rv1-FOLH1-oe) were comparable to that of [Ga-68]Ga-P16-093 and [Lu-177]Lu-PSMA-617, respectively. Specific cellular uptake was determined with or without the competitive blocking agent (2 mu M of "cold" PSMA-11). Cellular binding and internalization showed a time-dependent increase over 2 h at 37 degrees 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-68]Ga-1 and [Lu-177]Lu-1 displayed excellent uptake and retention in the tumor. Results indicate that [Ga-68]Ga/[Lu-177]Lu-1 (Ga-68]Ga/[Lu-177]Lu-AZ-093) is potentially useful as PSMA-targeting agent for both diagnosis and radiotherapy of prostate cancer.