Novel [ 68 Ga/ 177 Lu]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, [ 68 Ga]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, [ 177 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 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 [ 68 Ga]GaCl 3 or [ 177 Lu]LuCl 3 in a sodium acetate buffer solution (pH 4-5) at 50 °C in 5 to 15 min produced either [ 68 Ga]Ga- 1 or [ 177 Lu]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 [ 68 Ga]Ga-P16-093 and [ 177 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 [ 68 Ga]Ga- 1 and [ 177 Lu]Lu- 1 displayed excellent uptake and retention in the tumor. Results indicate that [ 68 Ga]Ga/[ 177 Lu]Lu- 1 ( 68 Ga]Ga/[ 177 Lu]Lu-AZ-093) is potentially useful as PSMA-targeting agent for both diagnosis and radiotherapy of prostate cancer.