Development of a Neurotensin-Derived 68Ga-Labeled PET Ligand with High In Vivo Stability for Imaging of NTS1 Receptor-Expressing Tumors
Creators: name: Schindler, Lisa
name: Moosbauer, Jutta
name: Schmidt, Daniel
name: Spruss, Thilo
name: Grätz, Lukas
name: Lüdeke, Steffen
name: Hofheinz, Frank
name: Meister, Sebastian
name: Echtenacher, Bernd
name: Bernhardt, Günther
name: Pietzsch, Jens
name: Hellwig, Dirk
name: Keller, Max
Publisher: name: Universität Regensburg
Year: 2022
Subjects: subject: SOLID-PHASE SYNTHESIS; NEUROPEPTIDE-Y; HIGH-AFFINITY; EMISSION-TOMOGRAPHY; BINDING-SITE; ANALOGS; PEPTIDE; BIODISTRIBUTION; CANCER; PROBES; positron emission tomography; tumor imaging; PET ligand; neurotensin NTS1 receptor; NT(8-13)
subject: 610 Medizin
subject: 615 Pharmazie

description: 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. 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 F-18- or Ga-68-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), 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-omega-carbamoylated arginine side chain. Insertion of Ga3+ in the DOTA chelator gave potential PET ligands that were evaluated concerning NTS1R affinity (range of K-i values: 1.2-21 nM) and plasma stability. Four candidates were labeled with Ga-68(3+) and used for biodistribution studies in HT-29 tumor-bearing mice. [Ga-68]UR-LS130 ([Ga-68]56), containing an N-terminal methyl group and a beta,beta-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 [Ga-68]56 in the tumor was NTS1R-mediated, as proven by blocking studies.