Bioconjugate Chemistry
Bioconjugate Chemistry
5 years ago

p-NO2–Bn–H4neunpa and H4neunpa–Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and 111In Immuno-Single Photon Emission Computed Tomography Imaging

p-NO2–Bn–H4neunpa and H4neunpa–Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and 111In Immuno-Single Photon Emission Computed Tomography Imaging
Maria de Guadalupe Jaraquemada-Peláez, Julie Rousseau, François Bénard, Una Jermilova, Ivica Bratanovic, Nadine Colpo, Karen Arane, Caterina F. Ramogida, Paul Schaffer, Iulia Dude, Gemma M. Dias, Chris Orvig, Sarah Spreckelmeyer
Potentially nonadentate (N5O4) bifunctional chelator p-SCN–Bn–H4neunpa and its immunoconjugate H4neunpa–trastuzumab for 111In radiolabeling are synthesized. The ability of p-SCN–Bn–H4neunpa and H4neunpa–trastuzumab to quantitatively radiolabel 111InCl3 at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In3+, Bi3+, and La3+ resulted in high conditional stability constant (pM) values. In vitro human serum stability assays have demonstrated both 111In complexes to have high stability over 5 days. Mouse biodistribution of [111In][In(p-NO2–Bn–neunpa)]−, compared to that of [111In][In(p-NH2–Bn–CHX-A″–diethylenetriamine pentaacetic acid (DTPA))]2–, at 1, 4, and 24 h shows fast clearance of both complexes from the mice within 24 h. In a second mouse biodistribution study, the immunoconjugates 111In-neunpa–trastuzumab and 111In–CHX-A″–DTPA–trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of 111In-neunpa–trastuzumab compared to that of 111In–CHX-A″–DTPA–trastuzumab. These results were also confirmed by immuno-single photon emission computed tomography (immuno-SPECT) imaging in vivo. These initial investigations reveal the acyclic bifunctional chelator p-SCN–Bn–H4neunpa to be a promising chelator for 111In (and other radiometals) with high in vitro stability and also show H4neunpa–trastuzumab to be an excellent 111In chelator with promising biodistribution in mice.

Publisher URL: http://dx.doi.org/10.1021/acs.bioconjchem.7b00311

DOI: 10.1021/acs.bioconjchem.7b00311

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