Mono‐Ethyl‐Phosphonates: Functional Group Masking Strategy to Stabilize and Optimize the Pharmacokinetics of Rare Earth Radiochelates

Prodrug strategies are widely used to enhance the pharmacokinetics of organic, small molecule drugs. Herein, this approach to rare earth coordination complexes is adopted with potential applications as diagnostic and therapeutic radiopharmaceuticals. Previously, the chelator m ‐phospatcn (H 4 L2) is identified as suitable for radiolabeling with 44 Sc and 177 Lu at room temperature. However, functionalizing H 4 L2 for targeting vector conjugation destabilizes the 44 Sc chelates, leading to increased blood retention, liver accumulation, and bone deposition. To address this, an ethyl group to mask one phosphonate oxygen (H 3 L2‐Et) is introduced. Spectrophotometric studies reveal reduced thermodynamic stability for [Sc(L2‐Et)] and [Lu(L2‐Et)] when compared with their phosphonate parent complexes. Radiolabeling with 44 Sc and 177 Lu remains efficient at ≤ 40 °C (155‐906 mCi μmol −1 ) with corresponding radiochelates remaining >87% and >98% inert in plasma after one isotope half‐life. In vivo biodistribution experiments indicate reduced blood retention and bone uptake for the lead model‐bifunctional [ 44 Sc][Sc(L2‐Et‐Aga)]. prostate specific membrane antigen (PSMA)‐targeted derivative, L2‐Et‐aga‐DUPA, affords 44 Sc and 177 Lu radiochemical complexes at ≤40 °C and selectively localizes in PSMA‐expressing tumors with minimal off‐target uptake.