Development of Highly Potent Clinical Candidates for Theranostic Applications against Cholecystokinin‑2 Receptor Positive Cancers

Peptide receptor radionuclide therapy (PRRT) is a promising form of systemic radiation therapy designed to eradicate cancer. Cholecystokinin-2 receptor (CCK2R) is an important molecular target that is highly expressed in a range of cancers. This study describes the synthesis and in vivo characterization of a novel series of 177Lu-labeled peptides ([177Lu]Lu-2b–4b) in comparison with the reference CCK2R-targeting peptide CP04 ([177Lu]Lu-1b). [177Lu]Lu-1b-4b showed high chemical purity (HPLC ≥ 94%), low Log D7.4 (−4.09 to −4.55) with strong binding affinity to CCK2R (KD 0.097–1.61 nM), and relatively high protein binding (55.6–80.2%) and internalization (40–67%). Biodistribution studies of the novel 177Lu-labeled peptides in tumors (AR42J and A431-CCK2R) showed uptake one- to eight-fold greater than the reference compound CP04 at 1, 24, and 48 h. Rapid clearance and high tumor uptake and retention were established for [177Lu]Lu-2b–4b, making these compounds excellent candidates for theranostic applications against CCK2R-expressing tumors.肽受体放射性核素治疗（Peptide receptor radionuclide therapy, PRRT）是一种极具应用前景的系统性放射治疗手段，旨在根治恶性肿瘤。胆囊收缩素2受体（Cholecystokinin-2 receptor, CCK2R）是一类重要的分子靶点，在多种恶性肿瘤中均呈高表达。本研究报道了一系列新型¹⁷⁷Lu标记肽（[¹⁷⁷Lu]Lu-2b–4b）的合成及体内表征，并与靶向CCK2R的参比肽CP04（[¹⁷⁷Lu]Lu-1b）进行了对照研究。结果显示，[¹⁷⁷Lu]Lu-1b~4b均具有较高的化学纯度（高效液相色谱High Performance Liquid Chromatography, HPLC≥94%），pH7.4条件下的脂水分配系数Log D7.4介于-4.09至-4.55之间，对CCK2R具有较强的结合亲和力（解离常数Dissociation Constant, KD为0.097~1.61 nM），同时具备相对较高的蛋白结合率（55.6%~80.2%）与细胞内化效率（40%~67%）。针对AR42J及A431-CCK2R肿瘤模型开展的新型¹⁷⁷Lu标记肽生物分布研究表明，在给药后1、24及48小时，该系列肽的肿瘤摄取量较参比化合物CP04高出1~8倍。[¹⁷⁷Lu]Lu-2b~4b展现出快速体内清除、高肿瘤摄取与滞留的优良特性，使其成为针对CCK2R阳性肿瘤开展诊疗一体化应用的极具潜力的候选化合物。