Development of a Neurotensin-Derived Ga-Labeled PET Ligand with High In Vivo Stability for Imaging of NTS Receptor-Expressing Tumors.

Overexpression of the neurotensin receptor type 1 (NTSR), a peptide receptor located at the plasma membrane, has been reported for a variety of malignant tumors. Thus, targeting the NTSR with F- or Ga-labeled ligands is considered a straightforward approach towards in vivo imaging of NTSR-expressing tumors via positron emission tomography (PET). The development of suitable peptidic NTSR PET ligands derived from neurotensin is challenging due to proteolytic degradation. In this study, we prepared a series of NTSR PET ligands based on the C-terminal fragment of neurotensin (NT(8-13), Arg-Arg-Pro-Tyr-Ile-Leu) by attachment of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) via an -carbamoylated arginine side chain. Insertion of Ga in the DOTA chelator gave potential PET ligands that were evaluated concerning NTSR affinity (range of values: 1.2-21 nM) and plasma stability. Four candidates were labeled with Ga and used for biodistribution studies in HT-29 tumor-bearing mice. [Ga]UR-LS130 ([Ga]), containing an N-terminal methyl group and a ,-dimethylated tyrosine instead of Tyr, 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 [Ga] in the tumor was NTSR-mediated, as proven by blocking studies.