Development of a Neurotensin-Derived 68 Ga-Labeled PET Ligand with High In Vivo Stability for Imaging of NTS 1 Receptor-Expressing Tumors.

Overexpression of the neurotensin receptor type 1 (NTS 1 R), a peptide receptor located at the plasma membrane, has been reported for a variety of malignant tumors. Thus, targeting the NTS 1 R with 18 F- or 68 Ga-labeled ligands is considered a straightforward approach towards in vivo imaging of NTS 1 R-expressing tumors via positron emission tomography (PET). The development of suitable peptidic NTS 1 R PET ligands derived from neurotensin is challenging due to proteolytic degradation. In this study, we prepared a series of NTS 1 R PET ligands based on the C-terminal fragment of neurotensin (NT(8-13), Arg 8 -Arg 9 -Pro 10 -Tyr 11 -Ile 12 -Leu 13 ) by attachment of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) via an N ω -carbamoylated arginine side chain. Insertion of Ga 3+ in the DOTA chelator gave potential PET ligands that were evaluated concerning NTS 1 R affinity (range of K i values: 1.2-21 nM) and plasma stability. Four candidates were labeled with 68 Ga 3+ and used for biodistribution studies in HT-29 tumor-bearing mice. [ 68 Ga]UR-LS130 ([ 68 Ga] 56 ), containing an N-terminal methyl group and a β , β -dimethylated tyrosine instead of Tyr 11 , 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 [ 68 Ga] 56 in the tumor was NTS 1 R-mediated, as proven by blocking studies.