Automated radiosynthesis and preclinical evaluation of Al[18F]F-NOTA-P-GnRH for PET imaging of GnRH receptor-positive tumors
Automated radiosynthesis and preclinical evaluation of Al[18F]F-NOTA-P-GnRH for PET imaging of GnRH receptor-positive tumors
复制标题
Al[F-18]F-NOTA-P-GnRH 的自动放射合成和临床前评估，用于 GnRH 受体阳性肿瘤的 PET 成像
DOI：
10.1016/j.nucmedbio.2020.02.004
复制
发表时间：
2020-03-01
影响因子：
3.1
通讯作者：
Hu, Kongzhen
中科院分区：
文献类型：
--
作者：
Huang, Shun;Wu, Hubing;Hu, Kongzhen
简介：促性腺激素释放激素（GnRH）受体在许多人类肿瘤中过表达。之前我们开发了一种f -18标记的GnRH肽。尽管在PC-3异种移植模型中，通过显微PET成像可以清楚地看到GnRH靶向PET探针，但由于复杂的标记程序、较差的放射化学产率以及GnRH受体阴性组织中不必要的积累，该探针的临床应用受到了限制。在这项研究中，我们设计了一种新的f -18标记的GnRH肽，更适合临床开发。方法：在改进的PET-MF-2V-IT-I合成模块上使用Al[F-18]F配合物合成GnRH肽类似物NOTA-P-GnRH，并用F-18自动放射性标记。采用体外竞争结合法测定AIF-NOTA-P-GnRH和NOTA-P-GnRH的受体亲和力。体外表征分别测定了稳定性和分配系数。Al[F-18]F-NOTA-P-GnRH的动态微pet和生物分布研究在异种移植肿瘤小鼠模型中进行了评估。结果：Al[F-18]F-NOTA-P-GnRH的全放射化学合成和纯化在35 min内完成，衰变校正产率为35 +/- 10%。Al[F-18]F-NOTA-P-GnRH的logP值为-2.74 +/- 0.04，示踪剂在磷酸盐缓冲盐水、牛和人血清中稳定。AlF-NOTA-P-GnRH和NOTA-P-GnRH的IC50值分别为116 nM和56.2 nM。动态PET成像和离体生物分布分析显示，Al[F-18]F-NOTA-P-GnRH在PC-3和MDA-MB-231异种移植肿瘤中均有清晰的描述。结论：Al[F-18]F-NOTA-P-GnRH可在市售的自动合成模块上高效合成，具有用于GnRH受体阳性肿瘤临床诊断的潜力。知识的进步：我们的研究开发了一种新的f -18标记的GnRH示踪剂的自动放射性合成和未来临床应用的预评估。对患者护理的启示：GnRH表达的定量和无创成像将为癌症患者的诊断和治疗提供信息。(C) 2020爱思唯尔公司版权所有。
Introduction: Gonadotropin releasing hormone (GnRH) receptor is overexpressed in many human tumors. Previously we developed a F-18-labelled GnRH peptide. Although the GnRH-targeted PET probe can be clearly visualized by microPET imaging in a PC-3 xenograft model, clinical applications of the probe have been limited by complex labeling procedures, poor radiochemical yield, and unwanted accumulation in GnRH receptor negative tissues. In this study, we have designed a new F-18-labelled GnRH peptide that is more amenable to clinical development.Methods: GnRH peptide analogues NOTA-P-GnRH was synthesized and automated radiolabeled with F-18 using a Al[F-18]F complex on a modified PET-MF-2V-IT-I synthesis module. The GnRH receptor affinities of AIF-NOTA-P-GnRH and NOTA-P-GnRH were determined by in vitro competitive binding assay. For in vitro characterization determination of stability and partition coefficients were carried out, respectively. Dynamic microPET and biodistribution studies of Al[F-18]F-NOTA-P-GnRH were evaluated in xenograft tumor mouse models.Results: The total radiochemical synthesis and purification of Al[F-18]F-NOTA-P-GnRH was completed within 35 min with a decay-corrected yield of 35 +/- 10%. The logP value of Al[F-18]F-NOTA-P-GnRH was -2.74 +/- 0.04 and the tracer was stable in phosphate-buffered saline, and bovine and human serum. The IC50 values of AlF-NOTA-P-GnRH and NOTA-P-GnRH were 116 nM and 56.2 nM, respectively. Dynamic PET imaging together with ex vivo biodistribution analyses revealed that Al[F-18]F-NOTA-P-GnRH was clearly delineated in both PC-3 and MDA-MB-231 xenografted tumors.Conclusion: Al[F-18]F-NOTA-P-GnRH can be efficiently produced on a commercially available automated synthesis module and has potential for use in clinical diagnosis of GnRH receptor-positive tumors.Advances in knowledge: Our studies developed the automated radiosynthesis of a new F-18-labelled GnRH tracer and predinical evaluation for future clinical application.Implications for patient care: Quantitative and noninvasive imaging of GnRH expression would provide information for diagnosis and treatment of cancer patients. (C) 2020 Elsevier Inc. All rights reserved.