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New chelators for radiopharmaceutical chemistry

University of British Columbia

This thesis presents studies on a new family of oxine (8-hydroxyquinoline) based acyclic chelators for application to radiometals (e.g., ⁶⁴Cu, ⁶⁷/⁶⁸Ga, ¹¹¹In) in nuclear medicine. Picolinic acid-based chelators (“pa” family) are reported as excellent radiometal chelators by our group’s previous study. Further development leads to the next generation chelators – the “ox” family (8-hydroxyquinoline). H₂hox showed a marked improvement from its “pa” counterpart, H₂dedpa, including an easy preparation, single complex species in a broad pH range (1-11) and high log KML (34.4) and pM (28.3) values. H₂hox showed fast (5 minutes) and quantitative ⁶⁸Ga labelling at room temperature with a concentration as low as 10-⁷ M and obtained a high molar activity. Excellent in vitro and in vivo stability was confirmed with plasma challenge experiments and dynamic PET imaging. The chelation enhanced fluorescence emission property was used directly to investigate the cellular distribution of [Ga(hox)]⁺ and showed the potential for dual channel imaging. Expanding from the lead chelator, H₂CHXhox was then synthesized by incorporating a cyclohexane (CHX) in the backbone to pre-organise the chelator and showed a great improvement on the kinetic inertness and thermodynamic stability. H₂C3hox was prepared by adding one more carbon to the backbone of H₂hox to obtain a 6-membered chelate ring, in order to investigate the preference of ring size on metal ion radii. H₂C3hox showed a decrease in solution stability, thought to be due to adopting a less stable conformation in the 6-membered chelate ring. H₄octox was designed with increased denticity (N₄O₄) vs H₂hox (N₄O₂) for larger metal ions and showed fast and stable chelation with metal ions (Y³⁺, In³⁺, La³⁺, Lu³⁺and Gd³⁺) in solution. Its in vitro stability with In³⁺ and Y³⁺ was proved using plasma and Fe³⁺ challenge experiments, and in vivo stability was confirmed with ¹¹¹In SPECT imaging. The 60-fold fluorescence emission increase when complexed with Y³⁺ can also be applied in probe design or bi-modal imaging. These studies have indicated that the new “ox” family of chelators is an excellent and useful platform in the development of radiometal-based pharmaceuticals.

Text

2019-04-29

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/69977

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/