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 (H₄L2) is identified as suitable for radiolabeling with ⁴⁴Sc and ¹⁷⁷Lu at room temperature. However, functionalizing H₄L2 for targeting vector conjugation destabilizes the ⁴⁴Sc chelates, leading to increased blood retention, liver accumulation, and bone deposition. To address this, an ethyl group to mask one phosphonate oxygen (H₃L2-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 ⁴⁴Sc and ¹⁷⁷Lu 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 [⁴⁴Sc][Sc(L2-Et-Aga)]. prostate specific membrane antigen (PSMA)-targeted derivative, L2-Et-aga-DUPA, affords ⁴⁴Sc and ¹⁷⁷Lu radiochemical complexes at ≤40 °C and selectively localizes in PSMA-expressing tumors with minimal off-target uptake.