Bergmann Ralf, Chollet Constance, Els-Heindl Sylvia, Ullrich Martin, Berndt Nicole, Pietzsch Jens, Máthé Domokos, Bachmann Michael, Beck-Sickinger Annette G
Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.
Oncotarget. 2021 Mar 2;12(5):450-474. doi: 10.18632/oncotarget.27895.
Imaging of Ghrelin receptors provides unique potential to gain deeper understanding on Ghrelin and its receptors in health and disease, in particular, in cancer. Ghrelin, an octanoylated 28-mer peptide hormone activates the constitutively active growth hormone secretagogue receptor type 1a (GHS-R1a) with nanomolar activity. We developed novel compounds, derived from the potent inverse agonist K-(D-1-Nal)-FwLL-NH but structurally varied by lysine conjugation with 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), palmitic acid and/or diethylene glycol (PEG2) to allow radiolabeling and improve pharmacokinetics, respectively. All compounds were tested for receptor binding, potency and efficacy , for biodistribution and -kinetics in rats and in preclinical prostate cancer models on mice. Radiolabeling with Cu-64 and Ga-68 was successfully achieved. The Cu-64- or Ga-68-NODAGA-NH-K-K-(D-1-NaI)-F-w-L-L-NH radiotracer were specifically accumulated by the GHS-R1a in xenotransplanted human prostate tumor models (PC-3, DU-145) in mice. The tumors were clearly delineated by PET. The radiotracer uptake was also partially blocked by K-(D-1-Nal)-FwLL-NH in stomach and thyroid. The presence of the GHS-R1a was also confirmed by immunohistology. In the arterial rat blood plasma, only the original compounds were found. The Cu-64 or Ga-68-NODAGA-NH-K-K-(D-1-NaI)-F-w-L-L-NH radiolabeled inverse agonists turned out to be potent and safe. Due to their easy synthesis, high affinity, medium potency, metabolic stability, and the suitable pharmacokinetic profiles, they are excellent tools for imaging and quantitation of GHS-R1a expression in normal and cancer tissues by PET. These compounds can be used as novel biomarkers of the Ghrelin system in precision medicine.
胃饥饿素受体成像为更深入了解胃饥饿素及其受体在健康和疾病（尤其是癌症）中的作用提供了独特的潜力。胃饥饿素是一种辛酰化的28肽激素，能以纳摩尔活性激活组成型活性生长激素促分泌素受体1a型（GHS-R1a）。我们开发了新型化合物，其衍生自强效反向激动剂K-(D-1-Nal)-FwLL-NH，但在结构上通过赖氨酸与1,4,7-三氮杂环壬烷、1-戊二酸-4,7-乙酸（NODAGA）、棕榈酸和/或二甘醇（PEG2）共轭而有所不同，分别用于实现放射性标记和改善药代动力学。所有化合物均在大鼠以及小鼠临床前前列腺癌模型中进行了受体结合、效力和功效、生物分布及动力学测试。成功实现了用铜-64和镓-68进行放射性标记。铜-64或镓-68-NODAGA-NH-K-K-(D-1-NaI)-F-w-L-L-NH放射性示踪剂在小鼠异种移植人前列腺肿瘤模型（PC-3、DU-145）中被GHS-R1a特异性摄取。通过PET可清晰勾勒出肿瘤。放射性示踪剂在胃和甲状腺中的摄取也被K-(D-1-Nal)-FwLL-NH部分阻断。免疫组织学也证实了GHS-R1a的存在。在大鼠动脉血浆中，仅发现了原始化合物。铜-64或镓-68-NODAGA-NH-K-K-(D-1-NaI)-F-w-L-L-NH放射性标记的反向激动剂结果显示强效且安全。由于其易于合成、高亲和力、中等效力、代谢稳定性以及合适的药代动力学特征，它们是通过PET成像和定量正常及癌组织中GHS-R1a表达的优秀工具。这些化合物可作为精准医学中胃饥饿素系统的新型生物标志物。
