Résumé
Aim/Introduction: Neurotensin receptor 2 (NTS 2) is a well-known mediator of central opioid-independent analgesia. NTS2 is also overexpressed in a variety of tumor types including prostate, pancreas and breast carcinoma (1,2). In this work, we describe the radiopharmaceutical characterization of [68 Ga]Ga-JMV7488, a new silylated peptide radiolabelled with gallium 68 ( 68 Ga) targeting NTS 2. Materials and Methods: JMV7488 (DOTA-βAla-βAla-Lys-Lys-Pro-(D)Trp-Ile-TMSAla-OH) was prepared using solid-phase synthesis, purified and then radiolabelled with gallium-68. In vitro characterization was carried out on the human colorectal adenocarcinoma HT29 cell line. In vivo pharmacology was assessed by μPET/ CT and animals sacrifice on HT29-xenografted nude mice.Results: [ 68 Ga]Ga-JMV7488 radiolabelling was achieved with moderate yield (53.9 ± 8.34 %) and high apparent molar activity (8.77 ± 1.23 GBq/μmol). It exhibited hydrophilic properties (octanol/PBS partition coefficient = -3.11 ± 0.24), suggesting renal clearance and low brain uptake. Saturation studies showed good affinity for NTS 2 (Kd = 37.10 ± 18.47 nM) and moderate selectivity (Kd NTS2 / Kd NTS1 = 15.90). The NTS 2-mediated internalized fraction reached 20.53 ± 6.50% at 10 min and remains stable until 60 min (23.98 ± 4.79 %), with very low membrane binding (< 8 %). These values are in accordance with the known internalization capacity of NTS2 upon agonistic stimulation. An early efflux was observed, increasing from 45.28 ± 6.85% at 5 min to 66.06 ± 8.55 % at 45 min. JMV7488 was characterized as a full agonist reaching 90.88 ± 11.49 % of normalized levocabastine maximum intracellular Ca2+ mobilization (EC 50 respectively 431 nM and 118 nM). In vivo [ 68 Ga]Ga-JMV7488 showed a moderate but promising tumor uptake of 0.5 % ID/g at 90 min post-injection. Kidneys (21.32 ± 7.04% ID/g) and prostate (4.56 ± 4.66% ID/g) demonstrated the highest normal uptake. Dynamic μPET/CT data are currently under analysis. Conclusion: We have synthesized and characterized radiolabelled [68 Ga]Ga-JMV7488, a full agonist at the NTS2, which binds to NTS 2 with high affinity and moderate selectivity. Compared with the literature (2), this novel analogue provides higher tumor uptake at later time point offering the potential to image and/or treat tumors over-expressing NTS2. The uptake in normal prostate represents a caveat for the use of NTS2 for diagnostic procedures in primary prostate cancers. We appeal for more studies aiming at deciphering the expression profile of NTS2 in human tumors. References: (1) Swift SL et al. Cancer Res. (2010) ; (2). Maschauer S et al. Bioorg Med Chem. (2015)