Phosphonate-Based Aza-Macrocycle Ligands for Low-Temperature, Stable Chelation of Medicinally Relevant Rare Earth Radiometals and Radiofluorination
Jennifer N. Whetter, Dariusz Śmiłowicz, K. Becker, Eduardo Aluicio‐Sarduy, Cormac A. A. Kelderman, Angus J. Koller, Owen M. Glaser, Axia Marlin, Shin Hye Ahn, Margarita N. Kretowicz, Jonathan W. Engle, Eszter Boros
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.