Synthesis and characterisation of DOTA-kisspeptin-10 as a potential gallium-68/lutetium-177 pan-tumour radiopharmaceutical

IF 3.3 4区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Neuroendocrinology Pub Date : 2025-01-07 DOI:10.1111/jne.13487

Janke Kleynhans, Robert Reeve, Cathryn H. S. Driver, Biljana Marjanovic-Painter, Mike Sathekge, Jan Rijn Zeevaart, Thomas Ebenhan, Robert P. Millar

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Abstract

Kisspeptin (KISS1) and its cognate receptor (KISS1R) are implicated in the progression of various cancers. A gallium-68 labelled kisspeptin-10 (KP10), the minimal biologically active structure, has potential as a pan-tumour radiopharmaceutical for the detection of cancers. Furthermore, a lutetium-177 labelled KP10 could find therapeutic application in treating oncological diseases. DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was attached to the NH2-terminus of KP10 as we posited from our previous publications that this modification would not impair biological activity. Here, we showed that the biological activity, as monitored by stimulation of inositol phosphate accumulation in HEK293 transfected with the KISS1R gene, was indeed similar for KP10 and DOTA-KP10. The optimisation of radiolabelling with gallium-68 and lutetium-177 is described. Stability in serum, plasma and whole blood was also investigated. Pharmacokinetics and biodistribution were established with micro-PET/CT (positron emission tomography/computerised tomography) and ex vivo measurements. Dynamic studies with micro-PET/CT demonstrated that background clearance for the radiopharmaceutical was rapid with a blood half-life of 18 ± 3 min. DOTA-KP10 demonstrated preserved functionality at KISS1R and good blood clearance. These results lay the foundation for the further development of DOTA-KP10 analogues that have high binding affinity along with proteolytic resistance.

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潜在镓-68/镥-177泛肿瘤放射性药物DOTA-kisspeptin-10的合成与表征。

Kisspeptin （KISS1）及其同源受体（KISS1R）与多种癌症的进展有关。镓-68标记的kisspeptin-10 （KP10）是最小的生物活性结构，具有作为泛肿瘤放射性药物检测癌症的潜力。此外，黄体177标记的KP10可用于治疗肿瘤疾病。DOTA（1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸）附着在KP10的nh2末端，因为我们从之前的出版物中假设这种修饰不会损害生物活性。在这里，我们发现，通过刺激转染KISS1R基因的HEK293中肌醇磷酸积累来监测，KP10和DOTA-KP10的生物活性确实相似。介绍了镓-68和镥-177放射性标记的优化方法。并对其在血清、血浆和全血中的稳定性进行了研究。通过微型pet /CT（正电子发射断层扫描/计算机断层扫描）和离体测量建立药代动力学和生物分布。微pet /CT动态研究表明，放射性药物的背景清除迅速，血液半衰期为18±3分钟。DOTA-KP10显示保留了KISS1R的功能和良好的血液清除。这些结果为进一步开发具有高结合亲和力和蛋白水解抗性的DOTA-KP10类似物奠定了基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Neuroendocrinology 医学-内分泌学与代谢

CiteScore

6.40

自引率

6.20%

发文量

137

审稿时长

4-8 weeks

期刊介绍： Journal of Neuroendocrinology provides the principal international focus for the newest ideas in classical neuroendocrinology and its expanding interface with the regulation of behavioural, cognitive, developmental, degenerative and metabolic processes. Through the rapid publication of original manuscripts and provocative review articles, it provides essential reading for basic scientists and clinicians researching in this rapidly expanding field. In determining content, the primary considerations are excellence, relevance and novelty. While Journal of Neuroendocrinology reflects the broad scientific and clinical interests of the BSN membership, the editorial team, led by Professor Julian Mercer, ensures that the journal’s ethos, authorship, content and purpose are those expected of a leading international publication.