H2azapa: a Versatile Acyclic Multifunctional Chelator for 67Ga, 64Cu, 111ln, and 177Lu.

Preliminary experiments with the novel acyclic triazole-containing bifunctional chelator H₂azapa and the radiometals 64Cu, 67Ga, 111In, and 177Lu have established its significant versatile potential as an alternative to 1,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid (DOTA) for metal-based radiopharmaceuticals. Unlike DOTA, H₂azapa radiolabels quantitatively with 64Cu, 67Ga, 111In, and 177Lu in 10 min at room temperature. In vitro competition experiments with human blood serum show that 64Cu remained predominantly chelate-bound, with only 2% transchelated to serum proteins after 20 h. Biodistribution experiments with [64Cu(azapa)] in mice reveal uptake in various organs, particularly in the liver, lungs, heart, intestines, and kidneys. When compared to [64Cu(DOTA)]2-, the lipophilic neutral [64Cu(azapa)] was cleared through the gastrointestinal tract and accumulated in the liver, which is common for lipophilic compounds or free 64Cu. The chelator H₂azapa is a model complex for a dick-based bifunctional chelating agent, and the lipophilic benzyl "place-holders" will be replaced by hydrophilic peptides to modulate the pharmacokinetics and direct activity away from the liver and gut. The solid-state molecular structure of [In(azapa)(H₂O)][ClO₄] reveals a very rare eight-coordinate distorted square antiprismatic geometry with one triazole arm bound, and the structure of [64Cu(azapa)] shows a distorted octahedral geometry. The present study demonstrates significant potential for bioconjugates of H₂azapa as alternatives to DOTA in copper-based radiopharmaceuticals, with the highly modular and "clickable" molecular scaffold of H₂azapa easily modified into a variety of bioconjugates. H₂azapa is a versatile addition to the "pa" family, joining the previously published H₂dedpa (67/68Ga and 64Cu), H₄octapa (111In, 177Lu, and 90Y), and H₅decapa (225Ac) to cover a wide range of important nuclides. [ABSTRACT FROM AUTHOR]