Preclinical Evaluation of Novel 64Cu-Labeled Gastrin-Releasing Peptide Receptor Bioconjugates for PET Imaging of Prostate Cancer,Bioconjugate Chemistry

当前位置： X-MOL 学术 › Bioconjugate Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Preclinical Evaluation of Novel 64Cu-Labeled Gastrin-Releasing Peptide Receptor Bioconjugates for PET Imaging of Prostate Cancer
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2021-01-12 , DOI: 10.1021/acs.bioconjchem.0c00656
George Makris ₁ , Antonio Shegani _{1,

2} , Pavithra H A Kankanamalage ₁ , Marina Kuchuk ₁ , Rajendra P Bandari ₃ , Charles J Smith _{1,

3,

4} , Heather M Hennkens _{1,

5}

Affiliation

We report herein the preclinical evaluation of new [⁶⁴Cu]Cu-gastrin-releasing peptide receptor (GRPR)-targeting tracers, employing the potent peptide antagonist _DPhe-Gln-Trp-Ala-VaI-Gly-His-Sta-Leu-NH₂ conjugated to NOTA (in 1) or NODAGA (in 2) chelators via a 6-aminohexanoic acid linker. The Cu-1/2 metalated peptides were synthesized by reacting 1/2 with CuCl₂ and were characterized by LC-ESI-MS and HR-ESI-MS. Cu-1/2 exhibited high GRPR-binding affinities with IC₅₀ values <3 nM, as measured in a competition assay using the GRPR-expressing human PC-3 prostate cancer cell line and [¹²⁵I]I-Tyr⁴-BBN as the competing ligand. Tracers [⁶⁴Cu]Cu-1/2 were prepared in quantitative radiochemical yield (by radio-HPLC), and their identities were confirmed by coelution with their Cu-1/2 standards via comparative HPLC studies. Lipophilicity was measured in 1-octanol/PBS (pH 7.4), and the negative log D_7.4 values (≤−1) confirmed the anticipated hydrophilic character for [⁶⁴Cu]Cu-1/2. Both tracers demonstrated excellent in vitro stability, with ≥98% remaining intact through 24 h at physiological conditions (PBS, pH 7.4, 37 °C). Biodistribution in PC-3 tumor-bearing mice demonstrated good tumor uptake (%ID/g at 4 h: 4.34 ± 0.71 for [⁶⁴Cu]Cu-1, 3.92 ± 1.03 for [⁶⁴Cu]Cu-2) and rapid renal clearance (≥87% ID at 4 h). Tumor uptake was receptor-mediated, as verified by parallel GRPR-blocking studies. Small-animal PET/CT imaging studies validated the biodistribution data. These preclinical data support that the [⁶⁴Cu]Cu-1/2 tracers show promise for further development as diagnostic PET imaging agents of GRPR-expressing tumors.

中文翻译：

用于前列腺癌 PET 成像的新型 64Cu 标记的胃泌素释放肽受体生物偶联物的临床前评估

我们在此报告了新的 [ ⁶⁴ Cu]Cu-胃泌素释放肽受体 (GRPR) 靶向示踪剂的临床前评估，采用强效肽拮抗剂_D Phe-Gln-Trp-Ala-VaI-Gly-His-Sta-Leu- NH ₂通过6-氨基己酸接头与NOTA（1中）或NODAGA（2中）螯合剂缀合。Cu- 1 / 2金属化肽是通过1 / 2与 CuCl ₂反应合成的，并通过 LC-ESI-MS 和 HR-ESI-MS 进行表征。Cu- 1 / 2表现出与 IC _{50 的}高 GRPR 结合亲和力值<3 nM，如在使用表达 GRPR 的人 PC-3 前列腺癌细胞系和 [ ¹²⁵ I]I-Tyr ⁴ -BBN 作为竞争配体的竞争测定中测量的。示踪剂 [ ⁶⁴ Cu] Cu- 1 / 2以定量放射化学产率制备（通过放射性 HPLC），并且通过比较 HPLC 研究与其 Cu- 1 / 2标准品共流出来确认它们的身份。在 1-辛醇/PBS (pH 7.4) 中测量亲脂性，负 log D _7.4值 (≤-1) 证实了 [ ⁶⁴ Cu] Cu- 1 / 2的预期亲水特性. 两种示踪剂都表现出出色的体外稳定性，在生理条件（PBS，pH 7.4，37 °C）下 24 小时内保持 ≥98% 的完整性。生物分布在PC-3荷瘤小鼠表现出良好的肿瘤摄取（％ID / g的4小时：4.34±0.71 [ ⁶⁴铜] CU- 1，3.92±1.03 [ ⁶⁴的Cu] CU- 2）和快速肾清除(≥87% ID 在 4 小时)。肿瘤摄取是受体介导的，正如平行 GRPR 阻断研究所证实的。小动物 PET/CT 成像研究验证了生物分布数据。这些临床前数据支持 [ ⁶⁴ Cu]Cu- 1 / 2 示踪剂显示出作为 GRPR 表达肿瘤的诊断 PET 显像剂的进一步发展的希望。

更新日期：2021-01-12

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11