Chelation in One Fell Swoop: Optimizing Ligands for Smaller Radiometal Ions

[^44/47Sc]Sc³⁺, [⁶⁸Ga]Ga³⁺, and [¹¹¹In]In³⁺ are the three most attractive trivalent smaller radiometalnuclides, offering a wide range of distinct properties (emission energies and types) in the toolbox of nuclear medicine. In this study, all three of the metal ions are successfully chelated using a new oxine-based hexadentate ligand, H₃glyox, which forms thermodynamically stable neutral complexes with exceptionally high pM values [pIn (34) > pSc (26) > pGa (24.9)]. X-ray diffraction single crystal structures with stable isotopes revealed that the ligand is highly preorganized and has a perfect fit to size cavity to form [Sc(glyox)(H₂O)] and [In(glyox)(H₂O)] complexes. Quantitative radiolabeling with gallium-68 (RCY > 95%, [L] = 10^-5 M) and indium-111 (RCY > 99%, [L] = 10^-8 M) was achieved under ambient conditions (RT, pH 7, and 15 min) with very high apparent molar activities of 750 MBq/μmol and 650 MBq/nmol, respectively. Preliminary quantitative radiolabeling of [⁴⁴Sc]ScCl₃ (RCY > 99%, [L] = 10^-6 M) was fast at room temperature (pH 7 and 10 min). In vitro experiments revealed exceptional stability of both [⁶⁸Ga]Ga(glyox) and [¹¹¹In]In(glyox) complexes against human serum (transchelation <2%) and its suitability for biological applications. Additionally, on chelation with metal ions, H₃glyox exhibits enhanced fluorescence, which was employed to determine the stability constants for Sc(glyox) in addition to the in-batch UV-vis spectrophotometric titrations; as a proof-of-concept these complexes were used to obtain fluorescence images of live HeLa cells using Sc(glyox) and Ga(glyox), confirming the viability of the cells. These initial investigations suggest H₃glyox to be a valuable chelator for radiometal-based diagnosis (nuclear and optical imaging) and therapy.