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

Abstract

Radioisotopes of fluorine ( 18 F), scandium ( 43/44 Sc, 47 Sc), lutetium ( 177 Lu), and yttrium ( 86 Y, 90 Y) 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 H 4 L2 and H 4 L3, two small-cavity macrocyclic chelator structural isomers bearing a single phosphonate functional group. Potentiometry and spectrophotometry were employed to determine H 4 L2 and H 4 L3′s ability to form a single [M(L)] − species with metals of different sizes (Sc 3+, Lu 3+, and Y 3+ ) under physiologically relevant conditions. NMR spectroscopy and density functional theory (DFT) calculations suggest modulation of H 4 L2 and H 4 L3′s inner-sphere hydration across the Sc 3+ /Lu 3+ /Y 3+ series. Radiochemical labeling experiments with 18 F, 44 Sc, 177 Lu, and 86 Y reveal that H 4 L2 selectively chelates radioscandium at room temperature with high apparent molar activity (AMA, 462 mCi/μmol), while radiofluorination remains inaccessible. In contrast, H 4 L3 enables room temperature radiochelation 44 Sc, 177 Lu, and 86 Y (AMA: 96–275 mCi/μmol) and incorporates 18 F via the Sc– 18 F methodology to form [ 18 F][ScF(L3)] 2– . In vivo biodistribution analysis at 1 h postinjection confirms the broad utility of H 4 L3: 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 18 F incorporation, to afford in vivo compatible complexes exceeds the clinical gold standard chelator DOTA and previously reported acyclic chelators, rendering H 4 L3 promising for prospective radiopharmaceutical applications.