Chelation of [ 111 In]In 3+ with the dual-size-selective macrocycles py-macrodipa and py 2 -macrodipa.

Indium-111 ( 111 In) is a diagnostic radiometal that is important in nuclear medicine for single-photon emission computed tomography (SPECT). In order to apply this radiometal, it needs to be stably chelated and conjugated to a targeting vector that delivers it to diseased tissue. Identifying effective chelators that are capable of binding and retaining [ 111 In]In 3+ in vivo is an important research area. In this study, two 18-membered macrocyclic chelators, py-macrodipa and py 2 -macrodipa, were investigated for their ability to form stable coordination complexes with In 3+ and to be effectively radiolabeled with [ 111 In]In 3+ . The In 3+ complexes of these two chelators were characterized by NMR spectroscopy, X-ray crystallography, and density functional theory calculations. These studies show that both py-macrodipa and py 2 -macrodipa form 8-coordinate In 3+ complexes and attain an asymmetric conformation, consistent with prior studies on this ligand class with small rare earth metal ions. Spectrophotometric titrations were carried out to determine the thermodynamic stability constants (log  K ML ) of [In(py-macrodipa)] + and [In(py 2 -macrodipa)] + , which were found to be 18.96(6) and 19.53(5), respectively, where the values in parentheses are the errors of the last significant figures obtained from the standard deviation from three independent replicates. Radiolabeling studies showed that py-macrodipa and py 2 -macrodipa can quantitatively be radiolabeled with [ 111 In]In 3+ at 25 °C within 5 min, even at ligand concentrations as low as 1 μM. The in vitro stability of the radiolabeled complexes was investigated in human serum at 37 °C, revealing that ∼90% of [ 111 In][In(py-macrodipa)] + and [ 111 In][In(py 2 -macrodipa)] + remained intact after 7 days. The biodistribution of these radiolabeled complexes in mice was investigated, showing lower uptake in the kidneys, liver, and blood at the 24 h mark compared to [ 111 In]InCl 3 . These results demonstrate the potential of py-macrodipa and py 2 -macrodipa as chelators for [ 111 In]In 3+ , suggesting their value for SPECT radiopharmaceuticals.