Phosphonate-Based\nAza-Macrocycle Ligands for Low-Temperature,\nStable Chelation of Medicinally Relevant Rare Earth Radiometals and\nRadiofluorination

Radioisotopes of fluorine (<sup>18</sup>F), scandium (<sup>43/44</sup>Sc, <sup>47</sup>Sc), lutetium (<sup>177</sup>Lu), and yttrium (<sup>86</sup>Y, <sup>90</sup>Y) have decay\nproperties ideally suited for\ntargeted nuclear imaging and therapy with small biologics, such as\npeptides and antibody fragments. However, a single-molecule strategy\nto introduce these radionuclides into radiopharmaceuticals under mild\nconditions to afford inert in vivo complexes is critically lacking.\nHere, we introduce H<sub>4</sub>L2 and H<sub>4</sub>L3, two small-cavity\nmacrocyclic chelator structural isomers bearing a single phosphonate\nfunctional group. Potentiometry and spectrophotometry were employed\nto determine H<sub>4</sub>L2 and H<sub>4</sub>L3′s ability\nto form a single [M(L)]<sup>−</sup> species with metals of\ndifferent sizes (Sc<sup>3+</sup>, Lu<sup>3+</sup>, and Y<sup>3+</sup>) under physiologically relevant conditions. NMR spectroscopy and\ndensity functional theory (DFT) calculations suggest modulation of\nH<sub>4</sub>L2 and H<sub>4</sub>L3′s inner-sphere hydration\nacross the Sc<sup>3+</sup>/Lu<sup>3+</sup>/Y<sup>3+</sup> series.\nRadiochemical labeling experiments with <sup>18</sup>F, <sup>44</sup>Sc, <sup>177</sup>Lu, and <sup>86</sup>Y reveal that H<sub>4</sub>L2 selectively chelates radioscandium at room temperature with high\napparent molar activity (AMA, 462 mCi/μmol), while radiofluorination\nremains inaccessible. In contrast, H<sub>4</sub>L3 enables room temperature\nradiochelation <sup>44</sup>Sc, <sup>177</sup>Lu, and <sup>86</sup>Y (AMA: 96–275 mCi/μmol) and incorporates <sup>18</sup>F via the Sc–<sup>18</sup>F methodology to form [<sup>18</sup>F][ScF(L3)]<sup>2–</sup>. In vivo biodistribution analysis\nat 1 h postinjection confirms the broad utility of H<sub>4</sub>L3:\nall four radiochemical complexes clear off-target organs and remain\n>98% intact in urine metabolite analyses. The scope of room temperature\nradiochemical labeling, paired with facile <sup>18</sup>F incorporation,\nto afford in vivo compatible complexes exceeds the clinical gold standard\nchelator DOTA and previously reported acyclic chelators, rendering\nH<sub>4</sub>L3 promising for prospective radiopharmaceutical applications.