Triazamacrocycle-based bicyclic peptide bioconjugates for nuclear medicine

Nuclear medicine plays a central role in cancer diagnosis and therapy through the use of radiopharmaceuticals. These agents combine a biological targeting vector labeled with a radionuclide, which can be a metal ion such as [68Ga]Ga3+ or [64Cu]Cu2+ for diagnosis, or [177Lu]Lu3+ for therapy. Efficient metal chelation is essential to ensure the in vivo stability of the metallic radiopharmaceutical. A well-established clinical example is the theranostic pair [68Ga]Ga-DOTA-TATE/[177Lu]Lu-DOTA-TATE targeting somatostatin receptor 2 (SSTR2) overexpressed in neuroendocrine tumors,[1] where the use of the same peptide vector (TATE or TOC) and chelator (DOTA) ensures comparable biodistribution in imaging and therapy. Cyclic polyamines such as DOTA are widely recognized for their excellent chelation properties.Peptides are well-known targeting vectors in nuclear medicine, particularly cyclic peptides that offer enhanced metabolic stability and high affinity for tumor-associated receptors.[2] Bicyclization represents a promising strategy to further improve peptide stability and preorganize the bioactive sequence. The resulting rigid two-loop architecture can enhance affinity and selectivity toward overexpressed complex tumor targets such as integrin αvβ3.[3] Incorporating a metal chelator as a central structural element within such a bicyclic architecture therefore offers the possibility of combining the structural role of the chelator in peptide bicyclization with its ability to complex radiometals.In this work, we explored a trifunctionalized triazacyclononane (tacn) chelator as a central scaffold for the development of [64Cu]Cu-labeled bicyclic peptides targeting integrin αvβ3. We will present the design and synthesis of tacn-based chelators and their bioconjugation to an RGD peptide, which recognizes and binds to integrin αvβ3. The resulting conjugate was radiolabeled with [64Cu]Cu2+, and its cellular internalization was subsequently evaluated in U87 glioblastoma cells overexpressing integrin αvβ3. Preliminary results from radiolabeling and biological studies will be presented, along with the development of the tacn scaffold as a central component for peptide bicyclization and the complexation of [64Cu]Cu2+.