Abstract / Summary
Abstract In vivo pretargeting is an emergent approach to nuclear imaging and radiopharmaceutical therapy that leverages the exquisite selectivity and affinity of full-length immunoglobulins while skirting their pharmacokinetic and dosimetric limitations. One particularly promising approach to pretargeting is predicated on the inverse electron-demand Diels−Alder reaction between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand. This methodology has been validated with a wide variety of antibody-antigen systems paired with radionuclides for positron emission tomography (PET), single photon emission computed tomography (SPECT), and radioimmunotherapy. The halogen group of the periodic table offers an abundance of isotopes that emit β−-particles (i.e. 131I), α-particles (i.e. 211At), and Auger electrons (i.e. 125I) for radiopharmaceutical therapy. Herein, we describe the synthesis and characterization of a pair of Tz radioligands containing 131I-labeled residualizing guanidinium prosthetic groups: iso-[131I]GMIB-PEG6-Tz and iso-[131I]GMIB-Tz. Subsequently, these two radioligands were used in conjunction with a TCO-bearing variant of the A33 antigen-targeting mAb huA33 (i.e. huA33-TCO) for in vivo pretargeting experiments in a murine model of colorectal carcinoma. The biodistribution and dosimetry data from these preclinical experiments suggested that the PEG6-containing radioligand offered a superior pharmacokinetic profile, and protocols were developed for the synthesis of iso-[211At]AGMB-PEG6-Tz. Finally, the in vivo behavior of iso-[211At]AGMB-PEG6-Tz was probed in both healthy mice and in a pretargeting system paired with huA33-TCO in a murine model of colorectal carcinoma.