LAUSR

Simple Summary Cancer diagnostics based on molecular imaging techniques such as positron emission tomography (PET) requires radiolabeled tracers, which are taken up by tumors. As the neurotensin receptor type 1 (NTS1R) is present in certain malignant tumors, radiolabeled NTS1R ligands can serve as molecular tools for tumor imaging. A straightforward approach for developing NTS1R PET ligands would be the preparation of fluorine-18 or gallium-68 labeled analogs of the peptide neurotensin. However, as neurotensin derivatives are prone to enzymatic cleavage, structural modifications are needed to prevent peptide degradation while retaining NTS1R affinity. Applying a new strategy for peptide stabilization, it is possible to develop a peptidic gallium-68 labeled NTS1R PET ligand with high in vivo stability and high NTS1R affinity. Investigations of the PET ligand in mice with subcutaneous NTS1R-positive tumors revealed the NTS1R-mediated visualization of the tumor. Future developments, such as NTS1R PET ligands with improved biodistribution, will benefit from these results. Abstract Overexpression of the neurotensin receptor type 1 (NTS1R), a peptide receptor located at the plasma membrane, has been reported for a variety of malignant tumors. Thus, targeting the NTS1R with 18F- or 68Ga-labeled ligands is considered a straightforward approach towards in vivo imaging of NTS1R-expressing tumors via positron emission tomography (PET). The development of suitable peptidic NTS1R PET ligands derived from neurotensin is challenging due to proteolytic degradation. In this study, we prepared a series of NTS1R PET ligands based on the C-terminal fragment of neurotensin (NT(8–13), Arg8-Arg9-Pro10-Tyr11-Ile12-Leu13) by attachment of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) via an Nω-carbamoylated arginine side chain. Insertion of Ga3+ in the DOTA chelator gave potential PET ligands that were evaluated concerning NTS1R affinity (range of Ki values: 1.2–21 nM) and plasma stability. Four candidates were labeled with 68Ga3+ and used for biodistribution studies in HT-29 tumor-bearing mice. [68Ga]UR-LS130 ([68Ga]56), containing an N-terminal methyl group and a β,β-dimethylated tyrosine instead of Tyr11, showed the highest in vivo stability and afforded a tumor-to-muscle ratio of 16 at 45 min p.i. Likewise, dynamic PET scans enabled a clear tumor visualization. The accumulation of [68Ga]56 in the tumor was NTS1R-mediated, as proven by blocking studies.