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

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.