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Synthesis and Evaluation of [18F]AlF-NOTA-c-DVAP: A Novel PET Probe for Imaging GRP78 in Cancer
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2024-03-30 , DOI: 10.1021/acs.molpharmaceut.3c01228 Jiawen Huang 1, 2 , Lu Bai 1, 2 , Dazhi Shi 1, 2 , Wenhao Jiang 1 , Pan Chen 3 , Ye Dong 2 , Xiaojun Zhang 2 , Jiangling Peng 4 , Jinqiang Hou 5, 6 , Yujing Lu 4 , Xiaohong Huang 1 , Ganghua Tang 2 , Shun Huang 1, 2
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2024-03-30 , DOI: 10.1021/acs.molpharmaceut.3c01228 Jiawen Huang 1, 2 , Lu Bai 1, 2 , Dazhi Shi 1, 2 , Wenhao Jiang 1 , Pan Chen 3 , Ye Dong 2 , Xiaojun Zhang 2 , Jiangling Peng 4 , Jinqiang Hou 5, 6 , Yujing Lu 4 , Xiaohong Huang 1 , Ganghua Tang 2 , Shun Huang 1, 2
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GRP78, a member of the HSP70 superfamily, is an endoplasmic reticulum chaperone protein overexpressed in various cancers, making it a promising target for cancer imaging and therapy. Positron emission tomography (PET) imaging offers unique advantages in real time, noninvasive tumor imaging, rendering it a suitable tool for targeting GRP78 in tumor imaging to guide targeted therapy. Several studies have reported successful tumor imaging using PET probes targeting GRP78. However, existing PET probes face challenges such as low tumor uptake, inadequate in vivo distribution, and high abdominal background signal. Therefore, this study introduces a novel peptide PET probe, [18F]AlF-NOTA-c-DVAP, for targeted tumor imaging of GRP78. [18F]AlF-NOTA-c-DVAP was radiolabeled with fluoride-18 using the aluminum-[18F]fluoride ([18F]AlF) method. The study assessed the partition coefficients, stability in vitro, and metabolic stability of [18F]AlF-NOTA-c-DVAP. Micro-PET imaging, pharmacokinetic analysis, and biodistribution studies were carried out in tumor-bearing mice to evaluate the probe’s performance. Docking studies and pharmacokinetic analyses of [18F]AlF-NOTA-c-DVAP were also performed. Immunohistochemical and immunofluorescence analyses were conducted to confirm GRP78 expression in tumor tissues. The probe’s binding affinity to GRP78 was analyzed by molecular docking simulation. [18F]AlF-NOTA-c-DVAP was radiolabeled in just 25 min with a high yield of 51 ± 16%, a radiochemical purity of 99%, and molar activity within the range of 20–50 GBq/μmol. [18F]AlF-NOTA-c-DVAP demonstrated high stability in vitro and in vivo, with a logD value of −3.41 ± 0.03. Dynamic PET imaging of [18F]AlF-NOTA-c-DVAP in tumors showed rapid uptake and sustained retention, with minimal background uptake. Biodistribution studies revealed rapid blood clearance and excretion through the kidneys following a single-compartment reversible metabolic model. In PET imaging, the T/M ratios for A549 tumors (high GRP78 expression), MDA-MB-231 tumors (medium expression), and HepG2 tumors (low expression) at 60 min postintravenous injection were 10.48 ± 1.39, 6.25 ± 0.47, and 3.15 ± 1.15% ID/g, respectively, indicating a positive correlation with GRP78 expression. This study demonstrates the feasibility of using [18F]AlF-NOTA-c-DVAP as a PET tracer for imaging GRP78 in tumors. The probe shows promising results in terms of stability, specificity, and tumor targeting. Further research may explore the clinical utility and potential therapeutic applications of this PET tracer for cancer diagnosis.
中文翻译：
[18F]AlF-NOTA-c-DVAP 的合成和评估：一种用于癌症 GRP78 成像的新型 PET 探针
GRP78 是 HSP70 超家族的成员，是一种在多种癌症中过度表达的内质网伴侣蛋白，使其成为癌症成像和治疗的有希望的靶点。正电子发射断层扫描（PET）成像在实时、无创肿瘤成像方面具有独特的优势，使其成为肿瘤成像中靶向GRP78以指导靶向治疗的合适工具。几项研究报告了使用针对 GRP78 的 PET 探针成功进行肿瘤成像。然而，现有的PET探针面临肿瘤摄取低、体内分布不充分、腹部背景信号高等挑战。因此，本研究引入了一种新型肽PET探针[ 18 F]AlF-NOTA-c- D VAP，用于GRP78的靶向肿瘤成像。使用铝-[ 18 F]氟化物([ 18 F]AlF)方法用氟化物-18对[ 18 F]AlF-NOTA-c- D VAP进行放射性标记。该研究评估了[ 18 F]AlF-NOTA-c- D VAP 的分配系数、体外稳定性和代谢稳定性。在荷瘤小鼠中进行了微型 PET 成像、药代动力学分析和生物分布研究，以评估探针的性能。还进行了[ 18 F]AlF-NOTA-c- D VAP 的对接研究和药代动力学分析。进行免疫组织化学和免疫荧光分析以确认肿瘤组织中GRP78的表达。通过分子对接模拟分析探针与GRP78的结合亲和力。 [ 18 F]AlF-NOTA-c- D VAP 在短短 25 分钟内即可完成放射性标记，收率高达 51 ± 16%，放射化学纯度为 99%，摩尔活度在 20–50 GBq/μmol 范围内。 [ 18 F]AlF-NOTA-c- D VAP 在体外和体内表现出高稳定性，logD 值为-3.41 ± 0.03。肿瘤中[ 18 F]AlF-NOTA-c- D VAP 的动态 PET 成像显示快速摄取和持续保留，背景摄取最小。生物分布研究表明，遵循单室可逆代谢模型，可快速血液清除并通过肾脏排泄。在PET成像中，静脉注射后60分钟A549肿瘤（GRP78高表达）、MDA-MB-231肿瘤（中表达）和HepG2肿瘤（低表达）的T/M比分别为10.48±1.39、6.25±0.47、和 3.15 ± 1.15% ID/g，分别表明与 GRP78 表达呈正相关。本研究证明了使用[ 18 F]AlF-NOTA-c -D VAP 作为 PET 示踪剂对肿瘤中 GRP78 进行成像的可行性。该探针在稳定性、特异性和肿瘤靶向方面显示出有希望的结果。进一步的研究可能会探索这种 PET 示踪剂在癌症诊断中的临床效用和潜在的治疗应用。
更新日期：2024-03-30
中文翻译：
[18F]AlF-NOTA-c-DVAP 的合成和评估：一种用于癌症 GRP78 成像的新型 PET 探针
GRP78 是 HSP70 超家族的成员，是一种在多种癌症中过度表达的内质网伴侣蛋白，使其成为癌症成像和治疗的有希望的靶点。正电子发射断层扫描（PET）成像在实时、无创肿瘤成像方面具有独特的优势，使其成为肿瘤成像中靶向GRP78以指导靶向治疗的合适工具。几项研究报告了使用针对 GRP78 的 PET 探针成功进行肿瘤成像。然而，现有的PET探针面临肿瘤摄取低、体内分布不充分、腹部背景信号高等挑战。因此，本研究引入了一种新型肽PET探针[ 18 F]AlF-NOTA-c- D VAP，用于GRP78的靶向肿瘤成像。使用铝-[ 18 F]氟化物([ 18 F]AlF)方法用氟化物-18对[ 18 F]AlF-NOTA-c- D VAP进行放射性标记。该研究评估了[ 18 F]AlF-NOTA-c- D VAP 的分配系数、体外稳定性和代谢稳定性。在荷瘤小鼠中进行了微型 PET 成像、药代动力学分析和生物分布研究，以评估探针的性能。还进行了[ 18 F]AlF-NOTA-c- D VAP 的对接研究和药代动力学分析。进行免疫组织化学和免疫荧光分析以确认肿瘤组织中GRP78的表达。通过分子对接模拟分析探针与GRP78的结合亲和力。 [ 18 F]AlF-NOTA-c- D VAP 在短短 25 分钟内即可完成放射性标记，收率高达 51 ± 16%，放射化学纯度为 99%，摩尔活度在 20–50 GBq/μmol 范围内。 [ 18 F]AlF-NOTA-c- D VAP 在体外和体内表现出高稳定性，logD 值为-3.41 ± 0.03。肿瘤中[ 18 F]AlF-NOTA-c- D VAP 的动态 PET 成像显示快速摄取和持续保留，背景摄取最小。生物分布研究表明，遵循单室可逆代谢模型，可快速血液清除并通过肾脏排泄。在PET成像中，静脉注射后60分钟A549肿瘤（GRP78高表达）、MDA-MB-231肿瘤（中表达）和HepG2肿瘤（低表达）的T/M比分别为10.48±1.39、6.25±0.47、和 3.15 ± 1.15% ID/g，分别表明与 GRP78 表达呈正相关。本研究证明了使用[ 18 F]AlF-NOTA-c -D VAP 作为 PET 示踪剂对肿瘤中 GRP78 进行成像的可行性。该探针在稳定性、特异性和肿瘤靶向方面显示出有希望的结果。进一步的研究可能会探索这种 PET 示踪剂在癌症诊断中的临床效用和潜在的治疗应用。
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