Klingler Maximilian, Rangger Christine, Summer Dominik, Kaeopookum Piriya, Decristoforo Clemens, von Guggenberg Elisabeth
Department of Nuclear Medicine, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
Pharmaceuticals (Basel). 2019 Jan 15;12(1):13. doi: 10.3390/ph12010013.
The high overexpression of cholecystokinin-2 receptors (CCK2R) in tumors, such as medullary thyroid carcinoma, allows for highly specific diagnostic and therapeutic targeting with radiolabeled peptide probes derived from natural ligands for the receptor. Based on the ideal imaging characteristics, high availability and low cost of technetium-99m (Tc)-labeled radiopharmaceuticals we have developed two hydrazinonicotinic acid (HYNIC) conjugated minigastrin analogs allowing labeling at high specific activity. The CCK2R targeting peptide conjugates show specific amino acid substitutions in the C-terminal receptor-specific sequence with the aim to increase stability and tumor targeting. The CCK2R affinity and the cell uptake of the new radioligands were analyzed using A431 human epidermoid carcinoma cells stably transfected with human CCK2R and mock transfected cells. Metabolic studies in BALB/c mice revealed a high resistance against enzymatic degradation for both radioligands. Biodistribution studies in tumor-xenografted athymic BALB/c nude mice at 1 h and 4 h p.i. showed that the two Tc-labeled compounds showed varying uptake in receptor expressing organs, stomach and pancreas (1.3⁻10.4% IA/g), as well as kidneys, the main route of excretion (7.8⁻19.9% IA/g). The tumor uptake in A431-CCK2R xenografts was 24.75 ± 4.38% IA/g for [Tc]Tc-HYNIC-MGS5 and 42.48 ± 6.99% IA/g for [Tc]Tc-HYNIC-MGS11 at 4 h p.i., whereas the tumor-to-kidney ratio was comparable (2.6⁻3.3). On demand availability and potential application for radioguided surgery of a Tc-labeled minigastrin analog support the further evaluation of these highly promising new compounds.
胆囊收缩素-2受体（CCK2R）在肿瘤（如甲状腺髓样癌）中高度过表达，这使得利用源自该受体天然配体的放射性标记肽探针进行高度特异性的诊断和治疗靶向成为可能。基于锝-99m（Tc）标记的放射性药物具有理想的成像特性、高可用性和低成本，我们开发了两种肼基烟酸（HYNIC）偶联的小胃泌素类似物，可实现高比活度标记。CCK2R靶向肽偶联物在C末端受体特异性序列中显示出特定的氨基酸取代，目的是提高稳定性和肿瘤靶向性。使用稳定转染人CCK2R的A431人表皮样癌细胞和mock转染细胞分析了新放射性配体的CCK2R亲和力和细胞摄取。BALB/c小鼠的代谢研究表明，两种放射性配体对酶降解均具有高抗性。在接种肿瘤的无胸腺BALB/c裸小鼠中进行的生物分布研究显示，在注射后1小时和4小时，两种Tc标记的化合物在表达受体的器官、胃和胰腺（1.3⁻10.4%注射剂量/克）以及主要排泄途径肾脏（7.8⁻19.9%注射剂量/克）中的摄取情况各不相同。在注射后4小时，[Tc]Tc-HYNIC-MGS5在A431-CCK2R异种移植瘤中的肿瘤摄取为24.75±4.38%注射剂量/克，[Tc]Tc-HYNIC-MGS11为42.48±6.99%注射剂量/克，而肿瘤与肾脏的比值相当（2.6⁻3.3）。Tc标记的小胃泌素类似物的按需可用性以及在放射性引导手术中的潜在应用支持对这些极具前景的新化合物进行进一步评估。
