Improved Nuclear Imaging by Pretargeting with Small Molecule

Radioactive-labeled peptides have found routine applications in nuclear medicine for the diagnosis (imaging) and therapy of different diseases including cancer. They exhibit advantageous characteristics as imaging agents and therapeutic drugs, such high specificity towards their molecular target (e.g., biomarkers expressed by cancer cells), favorable pharmacokinetics and reasonable costs of production. The elimination of radiopeptides from the body usually occurs via renal excretion. In some instances, the resulting uptake of radioactivity in radiation sensitive kidneys can be a limiting factor, especially if retained in the organ. This because of difficult delineation of lesions in the anatomic proximity of the organs during imaging or nephrotoxicity as the result of radiotherapy. These limitations of radiopeptides could be overcome by applying a novel concept, the so-called pre- targeting approach (PTA). In PTA, the tumor-targeting molecule is separated from the radioactive probe and both are injected one after another as a single agent. First, the tumor-targeting molecule, outfitted with a biorthogonal chemical handle, is injected and accumulates at the surface of tumors. In a second step, the radioactive probe, equipped with the corresponding counterpart for the chemical handle of the tumor-targeting molecule, is applied. Through highly specific and biorthogonal chemistry, the radioactive probe combines in vivo with the targeting molecule located on the tumor and therefore, the radioactivity accumulates at the diseased site. Excess of the low molecular weight radioactive probe not bound at the tumor clears rapidly through the kidneys without retention. Thus, the PTA has high potential to resolve issues of the clinical application of radiopeptides that exhibit high and persistent uptake in the kidneys. While the PTA with radioactive probes has been demonstrated preclinically multiple times with large protein such as tumor-targeting antibodies (mouse model), application of the concept to low- molecular weight peptides has yet not been explored. In this project, we will apply the PTA to different tumor-targeting peptides and investigate their potential for clinical applications in nuclear oncology with the aim to provide solutions for currently existing limitations.