Tripodal tris(hydroxypyridinone) ligands for immunoconjugate PET imaging with 89 Zr 4+ : comparison with desferrioxamine-B

• Published in: Dalton transactions : an international journal of inorganic chemistry 2015, Vol.44 (11), p.4884-4900
• Main Authors: Ma, Michelle T., Meszaros, Levente K., Paterson, Brett M., Berry, David J., Cooper, Maggie S., Ma, Yongmin, Hider, Robert C., Blower, Philip J.
• Format: Article
• Language: English
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/C4DT02978J

Due to its long half-life (78 h) and decay properties (77% electron capture, 23% β + , E max = 897 keV, E av = 397 keV, E γ = 909 keV, I γ = 100%) 89 Zr is an appealing radionuclide for immunoPET imaging with whole IgG antibodies. Derivatives of the siderophore desferrioxamine-B (H 3 DFO) are the most widely used bifunctional chelators for coordination of 89 Zr 4+ because the radiolabeling of the resulting immunoconjugates is rapid under mild conditions. 89 Zr-DFO complexes are reportedly stable in vitro but there is evidence that 89 Zr 4+ is released in vivo , and subsequently taken up by the skeleton. We have evaluated a novel tripodal tris(hydroxypyridinone) chelator, H 3 CP256 and its bifunctional maleimide derivative, H 3 YM103, for coordination of Zr 4+ and compared the NMR spectra, and the 89 Zr 4+ radiolabeling, antibody conjugation, serum stability and in vivo distribution of radiolabelled immunoconjugates with those of H 3 DFO and its analogues. H 3 CP256 coordinates 89 Zr 4+ at carrier-free concentrations forming [ 89 Zr(CP256)] + . Both H 3 DFO and H 3 CP256 were efficiently radiolabelled using [ 89 Zr(C 2 O 4 ) 4 ] 4− at ambient temperature in quantitative yield at pH 6–7 at millimolar concentrations of chelator. Competition experiments demonstrate that 89 Zr 4+ dissociates from [ 89 Zr(DFO)] + in the presence of one equivalent of H 3 CP256 (relative to H 3 DFO) at pH 6–7, resulting largely in [ 89 Zr(CP256)] + . To assess the stability of H 3 DFO and H 3 YM103 immunoconjugates radiolabelled with 89 Zr, maleimide derivatives of the chelators were conjugated to the monoclonal antibody trastuzumab via reduced cysteine side chains. Both immunoconjugates were labelled with 89 Zr 4+ in >98% yield at high specific activities and the labeled immunoconjugates were stable in serum with respect to dissociation of the radiometal. In vivo studies in mice indicate that 89 Zr 4+ dissociates from YM103-trastuzumab with significant amounts of activity becoming associated with bones and joints (25.88 ± 0.58% ID g −1 7 days post-injection). In contrast,