Research & Faculty

Default Header Image

p-NO2-Bn-H(4)neunpa and H(4)neunpa-Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and In-111 Immuno-Single Photon Emission Computed Tomography Imaging

Titlep-NO2-Bn-H(4)neunpa and H(4)neunpa-Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and In-111 Immuno-Single Photon Emission Computed Tomography Imaging
Publication TypeJournal Article
Year of Publication2017
AuthorsSpreckelmeyer, S, Ramogida, CF, Rousseau, J, Arane, K, Bratanovic, I, Colpo, N, Jermilova, U, Dias, GM, Dude, J, Jaraquemada-Pelaez, Mde Guadalu, Bénard, F, Schaffer, P, Orvig, C
JournalBioconjugate Chem.
Volume28
Pagination2145-2159
Date PublishedAUG
Type of Articleoriginal
ISSN1043-1802
Abstract

Potentially nonadentate (N5O4) bifunctional chelator p-SCN-Bn-H(4)neunpa and its immunoconjugate H(4)neunpa-trastuzumab for In-111 radiolabeling are synthesized. The ability of p-SCN-Bn H(4)neunpa and H(4)neunpa-trastuzumab to quantitatively radiolabel (InCl3)-In-111 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 In-111 complexes to have high stability over 5 days. Mouse biodistribution of {[}In-111]{[}In(p-NO2 Bn neunpa)](-), compared to that of {[}In-111]{[}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 In-neunpa trastuzumab and In-111-CHX-A{''}-DTPA-trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of In-111-neunpa-trastuzumab compared to that of In-111-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-H(4)neunpa to be a promising chelator for In-111 (and other radiometals) with high in vitro stability and also show H(4)neunpa trastuzumab to be an excellent In-111 chelator with promising biodistribution in mice.

DOI10.1021/acs.bioconjchem.7b00311