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.