¹⁸F- and ⁶⁸Ga-Labeled Neurotensin Peptides for PET Imaging of Neurotensin Receptor 1

Abstract

The neurotensin (NT) receptor-1 (NTS1) is overexpressed in a variety of carcinomas and is therefore an interesting target for imaging with positron emission tomography (PET). The aim of this study was the development of new NT derivatives based on the metabolically stable peptide sequence NLys-Lys-Pro-Tyr-Tle-Leu suitable for PET imaging. The NT peptides were synthesized by solid-phase supported peptide synthesis and elongated with respective chelators (NODA-GA, DOTA) for (68)Ga-labeling or propargylglycine for (18)F-labeling via copper-catalyzed azide-alkyne cycloaddition. Receptor affinities of the peptides for NTS1 were in the range of 19-110 nM. Biodistribution studies using HT29 tumor-bearing mice showed highest tumor uptake for [(68)Ga]6 and [(68)Ga]8 and specific binding in small-animal PET studies. The tumor uptake of (68)Ga-labeled peptides in vivo significantly correlated with the in vitro Ki values for NTS1. [(68)Ga]8 displayed an excellent tumor-to-background ratio and could therefore be considered as an appropriate molecular probe for NTS1 imaging by PET.

Radiopharmaceuticals for imaging and endoradiotherapy of neurotensin receptor‐positive tumors

“…52 A series of 68 Ga-and 18 F-labeled NT analogs bearing the same amino acid sequence, Nlys-Lys-Pro-Tyr-Tle-Leu, was reported by Maschauer et al (entries 5-8, Table 4). [53][54][55] This sequence is one of the few reported thus far that is stable not only in vitro but also in vivo. For 18 F-labeling, different 18 F-fluoroglycosyl azides were used as prosthetic groups, whereas for 68 Ga-labeling, NODAGA (1,4,7-triazacylononane-1-glutaric acid) or DOTA chelators were introduced at either the N-terminus or the ε-NH 2 group of Lys.…”

“…Peptides with free NH 2 -termini displayed high in vitro receptor affinities (19-20 nM), whereas peptides modified directly at the N-terminus showed significantly lower receptor affinities (110-180 nM). 55 The best in vivo performance-specifically, the highest tumor uptake values (1.6%ID/g, 60 minutes p.i.) and highest tumor-to-blood ratios (31 at 60 minutes p.i.…”

“…A series of 68 Ga‐ and 18 F‐labeled NT analogs bearing the same amino acid sequence, Nlys‐Lys‐Pro‐Tyr‐Tle‐Leu, was reported by Maschauer et al (entries 5–8, Table ) . This sequence is one of the few reported thus far that is stable not only in vitro but also in vivo.…”

“…7 Subsequently, the in vitro and in vivo properties of the resulting radiolabeled peptides were compared. Peptides with free NH 2 ‐termini displayed high in vitro receptor affinities (19–20 nM), whereas peptides modified directly at the N‐terminus showed significantly lower receptor affinities (110–180 nM) . The best in vivo performance—specifically, the highest tumor uptake values (1.6%ID/g, 60 minutes p.i.)…”

Evaluation of neurotensin receptor 1 as a potential imaging target in pancreatic ductal adenocarcinoma

“…Previously, our group and others have reported several tracers using radiolabeled NT analogue for human colon adenocarcinoma imaging (Alshoukr et al 2011; Deng et al 2015; Maschauer et al 2016; Schulz et al 2016; Wu et al 2014). In contrast, fluorescent imaging is relatively low cost, safe and easy to operate since it does not require ionizing radiation or radioactive materials, which make it easily applicable for intraoperative tumor margin identification (Chen et al 2008; Jennings and Long 2009; Liu et al 2013; Seibold et al 2014).…”