Challenges in the solution phase synthesis of PSMA-11 and PSMA-617: organic ligands for radiopharmaceutical preparations in prostate cancer medication

Patient specific treatments for different cancers are currently being actively addressed through nuclear medicine. More recently, the identification of biomarker namely; prostate-specific membrane antigen (PSMA) expressed on the prostate cancer cell surface has been considered as a turning point in prostate cancer management using radiopharmaceuticals. In this treatment method, apart from radionuclide, organic ligands that target PSMA constitute an essential component. PSMA-11 and PSMA-617 are two important ligands that form the radiopharmaceuticals, [68Ga]Ga-PSMA-11, [177Lu]Lu-PSMA-617, which are currently powering the prostate cancer management, especially metastatic castration resistant prostate cancer (mCRPC) in most part of the world. Identification of efficient synthetic routes towards these highly expensive ligands is an important prerequisite to make this treatment modality more popular. In this account, the synthetic challenges that we circumvent during the solution phase synthesis of PSMA-11 and PSMA-617, through different chemical synthetic routes are demonstrated. Post-synthesis, both the ligands, PSMA-11 and PSMA-617 were successfully radiolabelled using 68Ga, and 177Lu, respectively, to generate corresponding labelled products [68Ga]Ga-PSMA-11, and [177Lu]Lu-PSMA-617, in good radiochemical purity.