PDF(Pubmed)
Abstract：
BACKGROUND: The gastrin-releasing peptide receptor (GRPR) has been extensively studied as a biomolecular target for peptide-based radiotheranostics. However, the lack of metabolic stability and the rapid clearance of peptide radioligands, including radiolabeled GRPR-antagonists, often impede clinical application. Aiming at circumventing these drawbacks, we have designed three new GRPR-antagonist radioligands using [99mTc]Tc-DB15 ([99mTc]Tc-N4-AMA-DIG-DPhe-Gln-Trp-Ala-Val-Sar-His-Leu-NHEt; AMA: p-aminomethylaniline; DIG: diglycolate) as a motif, due to its high GRPR-affinity and stability to neprilysin (NEP). The new analogues carry the DOTAGA-chelator (1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid) through different linkers at the N-terminus to allow for labeling with the theranostic radionuclide pair In-111/Lu-177. After labeling with In-111 the following radioligands were evaluated: (i) [111In]In-AU-SAR-M1 ([111In]In-DOTAGA-AMA-DIG-DPhe-Gln-Trp-Ala-Val-Sar-His-Leu-NHEt), (ii) [111In]In-AU-SAR-M2 ([111In]In-[DOTAGA-Arg]AU-SAR-M1) and (iii) [111In]In-AU-SAR-M3 ([111In]In-[DOTAGA-DArg]AU-SAR-M1).
RESULTS: These radioligands were compared in a series of in vitro assays using prostate adenocarcinoma PC-3 cells and in murine models. They all displayed high and GRPR-specific uptake in PC-3 cells. Analysis of mice blood collected 5 min post-injection (pi) revealed similar or even higher metabolic stability of the new radioligands compared with [99mTc]Tc-DB15. The stability could be further increased when the mice were treated with Entresto® to in situ induce NEP-inhibition. In PC-3 xenograft-bearing mice, [111In]In-AU-SAR-M1 displayed the most favourable biodistribution profile, combining a good tumor retention with the highest tumor-to-organ ratios, with the kidneys as the dose-limiting organ.
CONCLUSIONS: These findings strongly point at AU-SAR-M1 as a promising radiotherapeutic candidate when labeled with Lu-177, or other medically appealing therapeutic radiometals, especially when combined with in situ NEP-inhibition. To this goal further investigations are currently pursued.
RESULTS: These radioligands were compared in a series of in vitro assays using prostate adenocarcinoma PC-3 cells and in murine models. They all displayed high and GRPR-specific uptake in PC-3 cells. Analysis of mice blood collected 5 min post-injection (pi) revealed similar or even higher metabolic stability of the new radioligands compared with [99mTc]Tc-DB15. The stability could be further increased when the mice were treated with Entresto® to in situ induce NEP-inhibition. In PC-3 xenograft-bearing mice, [111In]In-AU-SAR-M1 displayed the most favourable biodistribution profile, combining a good tumor retention with the highest tumor-to-organ ratios, with the kidneys as the dose-limiting organ.
CONCLUSIONS: These findings strongly point at AU-SAR-M1 as a promising radiotherapeutic candidate when labeled with Lu-177, or other medically appealing therapeutic radiometals, especially when combined with in situ NEP-inhibition. To this goal further investigations are currently pursued.
摘要：
背景：胃泌素释放肽受体（GRPR）已被广泛研究为基于肽的放射疗法的生物分子靶标。然而,缺乏代谢稳定性和肽放射性配体的快速清除，包括放射性标记的GRPR拮抗剂，往往阻碍临床应用。为了避免这些缺点，我们设计了三种新的GRPR拮抗剂放射性配体，使用[99mTc]Tc-DB15（[99mTc]Tc-N4-AMA-DIG-DPhe-Gln-Trp-Ala-Val-Sar-His-Leu-NHEt）作为基序，由于其高GRPR亲和力和稳定性的脑啡肽酶（NEP）。新的类似物在N末端通过不同的接头携带DOTAGA-螯合剂（1,4,7,10-四氮杂环十二烷-1-戊二酸-4,7,10-三乙酸），以允许用热学放射性核素对标记In-111/Lu-177。用In-111标记后，评估了以下放射性配体：（i）[111In]In-AU-SAR-M1（[111In]In-DOTAGA-AMA-DIG-DPhe-Gln-Trp-Ala-Val-Sar-His-Leu-NHEt），(ii)[111In]In-AU-SAR-M2([111In]In-[DOTAGA-Arg]AU-SAR-M1)和(iii)[111In]In-AU-SAR-M3([111In]In-[DOTAGA-DArg]AU-SAR-M1)。
结果:在一系列使用前列腺腺癌PC-3细胞的体外测定中和在鼠模型中比较了这些放射性配体。它们在PC-3细胞中均显示出高的GRPR特异性摄取。对注射后5分钟（pi）收集的小鼠血液的分析显示，与[99mTc]Tc-DB15相比，新放射性配体的代谢稳定性相似或甚至更高。当用Entresto®处理小鼠以原位诱导NEP抑制时,稳定性可以进一步增加。在携带PC-3异种移植物的小鼠中，[111In]In-AU-SAR-M1显示出最有利的生物分布特征，结合良好的肿瘤保留和最高的肿瘤器官比，以肾脏为剂量限制器官。
结论：这些发现强烈指出，AU-SAR-M1在标记Lu-177或其他具有医学吸引力的治疗放射性金属时，是一种有前途的放射治疗候选药物。特别是与原位NEP抑制结合时。为此，目前正在进行进一步的调查。
结果:在一系列使用前列腺腺癌PC-3细胞的体外测定中和在鼠模型中比较了这些放射性配体。它们在PC-3细胞中均显示出高的GRPR特异性摄取。对注射后5分钟（pi）收集的小鼠血液的分析显示，与[99mTc]Tc-DB15相比，新放射性配体的代谢稳定性相似或甚至更高。当用Entresto®处理小鼠以原位诱导NEP抑制时,稳定性可以进一步增加。在携带PC-3异种移植物的小鼠中，[111In]In-AU-SAR-M1显示出最有利的生物分布特征，结合良好的肿瘤保留和最高的肿瘤器官比，以肾脏为剂量限制器官。
结论：这些发现强烈指出，AU-SAR-M1在标记Lu-177或其他具有医学吸引力的治疗放射性金属时，是一种有前途的放射治疗候选药物。特别是与原位NEP抑制结合时。为此，目前正在进行进一步的调查。
