H 2azapa: A versatile acyclic multifunctional chelator for 67Ga, 64Cu, 111In, and 177Lu Journal Article
| Authors: | Bailey, G. A.; Price, E. W.; Zeglis, B. M.; Ferreira, C. L.; Boros, E.; Lacasse, M. J.; Patrick, B. O.; Lewis, J. S.; Adam, M. J.; Orvig, C. |
| Article Title: | H 2azapa: A versatile acyclic multifunctional chelator for 67Ga, 64Cu, 111In, and 177Lu |
| Abstract: | Preliminary experiments with the novel acyclic triazole-containing bifunctional chelator H 2azapa and the radiometals 64Cu, 67Ga, 111In, and 177Lu have established its significant versatile potential as an alternative to 1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for metal-based radiopharmaceuticals. Unlike DOTA, H 2azapa 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 H 2azapa is a model complex for a click-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)(H 2O)][ClO 4] 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 H 2azapa as alternatives to DOTA in copper-based radiopharmaceuticals, with the highly modular and "clickable" molecular scaffold of H 2azapa easily modified into a variety of bioconjugates. H 2azapa is a versatile addition to the "pa" family, joining the previously published H 2dedpa ( 67/68Ga and 64Cu), H 4octapa ( 111In, 177Lu, and 90Y), and H 5decapa ( 225Ac) to cover a wide range of important nuclides. © 2012 American Chemical Society. |
| Journal Title: | Inorganic Chemistry |
| Volume: | 51 |
| Issue: | 22 |
| ISSN: | 0020-1669 |
| Publisher: | ACS Publications |
| Date Published: | 2012-10-01 |
| Start Page: | 12575 |
| End Page: | 12589 |
| Language: | English |
| DOI: | 10.1021/ic302225z |
| PROVIDER: | scopus |
| PUBMED: | 23106422 |
| PMCID: | PMC4968691 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 December 2012" - "CODEN: INOCA" - "Source: Scopus" |
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