Endocrine Abstracts

The intrinsic selectivity and flexibility of bioorthogonal click chemistries make them an almost ideal synthetic methodology for the creation of radiolabeled PET imaging agents. One type of bioorthogonal reaction, the inverse electron demand Diels-Alder reaction between tetrazine and TCO, has particularly appealing characteristics for in vivo pretargeting applications. Simply put, the thrust of pretargeted imaging is to harness the exquisite tumor-targeting properties of antibodies while avoiding their slow pharmacokinetics and high background doses. To this end, pretargeting strategies decouple the targeting vector from the radioisotope at the time of injection. In the case of tetrazine/TCO pretargeting, a TCO-labeled antibody could be injected days ahead of the actual imaging procedure. Then, only hours before imaging, a radiolabeled small molecule is administered which travels through the blood with a dramatically reduced blood half-life, either binding to the TCO-labeled antibody or quickly clearing from the patient.

Pretargeted approaches hold the promise of producing high activity uptake in tumors with extremely low levels of off-target radiation in non-target organs. In essence, this negates the biggest drawback of radiolabeled antibodies: the high radiation dose delivered to healthy tissues during long circulation times. These preclinical approaches illustrate the tremendous promise of the tetrazine/TCO reaction, establishing the basis for a clinical application of the methodology. In this R01, our goal is to translate this tetrazine/TCO-based pretargeting strategy to the clinic and to show that this technology can be superior to traditional PET imaging approaches using directly radiolabeled antibodies.