Neurotensin receptor 1 (NTSR1) is overexpressed in most human pancreatic ductal adenocarcinomas. It makes it an attractive target for the development of pancreatic cancer imaging agents. In this study, we sought to develop a bimodal PET-fluorescent imaging agent capable of specifically targeting these receptors. Starting from the structure of a known NTSR1 agonist, a series of tracers was synthesized, radiometalated with gallium-68 and evaluated in vitro and in vivo, in mice bearing an AsPC-1 xenograft. PET imaging allowed us to identify the compound [ 68 Ga]Ga-NODAGA-Lys(Cy5**)-AEEAc-[Me-Arg 8 , Tle 12 ]-NT(7-13) as the one with the most promising biodistribution profile, characterized by high tumor uptake (2.56 ± 0.97 %ID/g, 1 h p.i.) and rapid elimination from non-targeted organs, through urinary excretion. Fluorescence imaging gave similar results. On this basis, fluorescence-guided resection of tumor masses was successfully carried out on a preclinical model.

Neurotensin receptor 1 (NTS1) is involved in the development and progression of numerous cancers, which makes it an interesting target for the development of diagnostic and therapeutic agents. A small molecule NTS1 antagonist, named [ 177 Lu]Lu-IPN01087, is currently evaluated in phase I/II clinical trials for the targeted therapy of neurotensin receptor-positive cancers. In this study, we synthesized seven compounds based on the structure of NTS1 antagonists, bearing different chelating agents, and radiolabeled them with gallium-68 for PET imaging. These compounds were evaluated in vitro and in vivo in mice bearing a HT-29 xenograft. The compound [ 68 Ga]Ga-bisNODAGA-16 showed a promising biodistribution profile with mainly signal in tumor (4.917 ± 0.776%ID/g, 2 h post-injection). Its rapid clearance from healthy tissues led to high tumor-to-organ ratios, resulting in highly contrasted PET images. These results were confirmed on subcutaneous xenografts of AsPC-1 tumor cells, a model of NTS1-positive human pancreatic adenocarcinoma.or DOTAGA chelators on a same molecule in order to increase clearance from blood and improve tumor-to-background ratios. This approach was inspired by the work of Roxin et al., who showed that the introduction of a metalfree DOTA on a 18 F-radiotracer could improve tumor uptake and increase renal excretion. 41