Phosphonate-Based Aza-Macrocycle Ligands for Low-Temperature, Stable Chelation of Medicinally Relevant Rare Earth Radiometals and Radiofluorination

Abstract

Radioisotopes of fluorine (¹⁸F), scandium (^43/44Sc, ⁴⁷Sc), lutetium (¹⁷⁷Lu), and yttrium (⁸⁶Y, ⁹⁰Y) have decay properties ideally suited for targeted nuclear imaging and therapy with small biologics, such as peptides and antibody fragments. However, a single-molecule strategy to introduce these radionuclides into radiopharmaceuticals under mild conditions to afford inert in vivo complexes is critically lacking. Here, we introduce H₄L2 and H₄L3, two small-cavity macrocyclic chelator structural isomers bearing a single phosphonate functional group. Potentiometry and spectrophotometry were employed to determine H₄L2 and H₄L3′s ability to form a single [M(L)]⁻ species with metals of different sizes (Sc³⁺, Lu³⁺, and Y³⁺) under physiologically relevant conditions. NMR spectroscopy and density functional theory (DFT) calculations suggest modulation of H₄L2 and H₄L3′s inner-sphere hydration across the Sc³⁺/Lu³⁺/Y³⁺ series. Radiochemical labeling experiments with ¹⁸F, ⁴⁴Sc, ¹⁷⁷Lu, and ⁸⁶Y reveal that H₄L2 selectively chelates radioscandium at room temperature with high apparent molar activity (AMA, 462 mCi/μmol), while radiofluorination remains inaccessible. In contrast, H₄L3 enables room temperature radiochelation ⁴⁴Sc, ¹⁷⁷Lu, and ⁸⁶Y (AMA: 96–275 mCi/μmol) and incorporates ¹⁸F via the Sc–¹⁸F methodology to form [¹⁸F][ScF(L3)]^2–. In vivo biodistribution analysis at 1 h postinjection confirms the broad utility of H₄L3: all four radiochemical complexes clear off-target organs and remain >98% intact in urine metabolite analyses. The scope of room temperature radiochemical labeling, paired with facile ¹⁸F incorporation, to afford in vivo compatible complexes exceeds the clinical gold standard chelator DOTA and previously reported acyclic chelators, rendering H₄L3 promising for prospective radiopharmaceutical applications.