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.