Adapting Solid Phase Radiometalation Photorelease to the Synthesis of 44Sc and 177Lu Radiopharmaceuticals

Synthetic methods that simplify and streamline radiopharmaceutical synthesis help expand utility and access of radiopharmaceuticals to greater patient populations. As radiochemical synthesis is inherently limited by the isotope's half-life, methods that shorten and simplify radiosynthesis and formulation, while also minimizing degradation prior to administration to the patient, are needed. Recently, we introduced solid phase radiometalation photorelease (SPRP) as a new strategy for the synthesis of 68Ga3+ and 64Cu-labeled radiopharmaceuticals. Herein, we expand SPRP to 44Sc3+ and 177Lu3+ and demonstrate its utility in synthesizing two targeted radiopharmaceuticals. Employing a series of model peptide constructs linked to the chelator AAZTA, which has been extensively validated for 44Sc3+, 177Lu3+, and more recently for 68Ga3+, we optimized radiochemical labeling conditions and photorelease with 44Sc3+ and 177Lu3+. Specifically, we show that radionuclide capture on resin is robust and high-yielding following 24-72 h of storage on solid-phase immobilized chelate (177Lu3+) and in the presence of excess target separation impurities such 1 mM calcium (target material for the cyclotron-production of 44Sc3+). The photochemical release of 177Lu3+ and 44Sc-labeled tracers was optimized by addition of ascorbate, an FDA-approved radical quencher, producing 40-60% nondecay-corrected, radiochemical conversion yields and >98% radiochemical purity. Finally, a proof of concept radiolabeling and subsequent preclinical PET-CT study with two targeted radiopharmaceuticals, 44Sc-AAZTA-Glu-PSMA-617 and 44Sc-DOTA-Lys-PSMA-617, successfully demonstrate the compatibility of SPRP with preclinically and clinically relevant rare earth isotopes.