神经降压素受体1型(NTS1R)的过表达,位于质膜的肽受体,已被报道为多种恶性肿瘤。因此,用18F或68Ga标记的配体靶向NTS1R被认为是通过正电子发射断层扫描(PET)对表达NTS1R的肿瘤进行体内成像的简单方法。源自神经降压素的合适肽NTS1RPET配体的开发由于蛋白水解降解而具有挑战性。在这项研究中,我们制备了一系列基于神经降压素C末端片段的NTS1RPET配体(NT(8-13),Arg8-Arg9-Pro10-Tyr11-Ile12-Leu13)通过Nω-氨基甲酰化精氨酸侧链连接螯合剂1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)。在DOTA螯合剂中插入Ga3可产生潜在的PET配体,对其进行了NTS1R亲和力(Ki值范围:1.2-21nM)和血浆稳定性评估。用68Ga3+标记四个候选物,并用于HT-29荷瘤小鼠中的生物分布研究。[68Ga]UR-LS130([68Ga]56),含有N-末端甲基和β,β-二甲基化酪氨酸代替Tyr11,显示出最高的体内稳定性,并在p.i.45分钟时提供16的肿瘤与肌肉的比率。同样,动态PET扫描可实现清晰的肿瘤可视化.[68Ga]56在肿瘤中的积累是NTS1R介导的,正如阻断研究所证明的那样。
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 18F- or 68Ga-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), Arg8-Arg9-Pro10-Tyr11-Ile12-Leu13) by attachment of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) via an Nω-carbamoylated arginine side chain. Insertion of Ga3+ in the DOTA chelator gave potential PET ligands that were evaluated concerning NTS1R affinity (range of Ki values: 1.2-21 nM) and plasma stability. Four candidates were labeled with 68Ga3+ and used for biodistribution studies in HT-29 tumor-bearing mice. [68Ga]UR-LS130 ([68Ga]56), containing an N-terminal methyl group and a β,β-dimethylated tyrosine instead of Tyr11, 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 [68Ga]56 in the tumor was NTS1R-mediated, as proven by blocking studies.