Peptides are ideal for theranostic development as they afford rapid target accumulation, fast clearance from background tissue, and exhibit good tissue penetration. Previously, we developed a novel series of peptides that presented discreet folding propensity leading to an optimal candidate [⁶⁸Ga]Ga-DOTA-GA1 ([D-Glu]₆-Ala-Tyr-NMeGly-Trp-NMeNle-Asp-Nal-NH₂) with 50 pM binding affinity against cholecystokinin-2 receptors (CCK₂R). However, we were confronted with challenges of unfavorably high renal uptake./nMethods: A structure activity relationship study was undertaken of the lead theranostic candidate. Prudent structural modifications were made to the peptide scaffold to evaluate the contributions of specific N-terminal residues to the overall biological activity. Optimal candidates were then evaluated in nude mice bearing transfected A431-CCK₂ tumors, and their biodistribution was quantitated ex vivo./nResults: We identified and confirmed that D-Glu³ to D-Ala³ substitution produced 2 optimal candidates, [⁶⁸Ga]Ga-DOTA-GA12 and [⁶⁸Ga]Ga-DOTA-GA13. These radiopeptides presented with high target/background ratios, enhanced tumor retention, excellent metabolic stability in plasma and mice organ homogenates, and a 4-fold reduction in renal uptake, significantly outperforming their non-alanine counterparts./nConclusions: Our study identified novel radiopharmaceutical candidates that target the CCK₂R. Their high tumor uptake and reduced renal accumulation warrant clinical translation./n

中文翻译：

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精密肽治疗诊断学：开发针对胆囊收缩素-2 受体的 N 至 C 末端优化治疗诊断学

肽是治疗诊断开发的理想选择，因为它们能够快速积累靶点、从背景组织中快速清除，并表现出良好的组织渗透性。此前，我们开发了一系列新颖的肽，这些肽具有谨慎的折叠倾向，从而产生了最佳候选[ ⁶⁸ Ga]Ga-DOTA- GA1（[D-Glu] ₆ -Ala-Tyr -N MeGly-Trp- N MeNle-Asp- Nal-NH ₂ ) 对胆囊收缩素-2 受体 (CCK ₂ R) 具有 50 pM 的结合亲和力。然而，我们面临着肾脏摄取过高的挑战。/n方法：对主要治疗诊断候选者进行了结构活性关系研究。对肽支架进行审慎的结构修饰，以评估特定N端残基对整体生物活性的贡献。然后在带有转染的 A431-CCK ₂肿瘤的裸鼠中评估最佳候选物，并在体外定量其生物分布。/n结果：我们鉴定并确认 D-Glu ³到 D-Ala ³的替代产生了 2 个最佳候选物，[ ⁶⁸ Ga]Ga-DOTA- GA12和[ ⁶⁸ Ga]Ga-DOTA- GA13。这些放射性肽具有高目标/背景比、增强的肿瘤保留、血浆和小鼠器官匀浆中优异的代谢稳定性以及肾脏摄取量减少 4 倍，显着优于非丙氨酸对应物。/n 结论：我们的研究发现了新的靶向 CCK ₂ R 的候选放射性药物。它们的高肿瘤摄取和减少的肾脏蓄积值得临床转化。/n