Radiolabeled R954 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography,Molecular Pharmaceutics

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Radiolabeled R954 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-02-02 00:00:00 , DOI: 10.1021/acs.molpharmaceut.6b01055
Hsiou-Ting Kuo ₁ , Jinhe Pan ₁ , Joseph Lau ₁ , Chengcheng Zhang ₁ , Jutta Zeisler ₁ , Nadine Colpo ₁ , François Bénard _{1,

2,

3} , Kuo-Shyan Lin _{1,

2,

3}

Affiliation

Peptide receptors have emerged as promising targets for diagnosis and therapy. The aberrant overexpression of these receptors in different cancer subtypes allows for the adoption of new treatment strategies that complement conventional chemotherapies. Bradykinin B1 receptor (B1R) is a G protein-coupled receptor that is overexpressed in many cancers, with limited expression in healthy tissues. Previously, we developed ⁶⁸Ga- and ¹⁸F-labeled derivatives of B1R antagonist peptides B9858 and B9958, and successfully targeted B1R-expressing tumor xenografts in vivo. R954 (Ac-Orn-Arg-Oic-Pro-Gly-αMePhe-Ser-d-2-Nal-Ile), a potent B1R antagonist, is reportedly more stable than B9858 against peptidase degradation. We evaluated two radiolabeled derivatives of R954 (⁶⁸Ga-HTK01083 and ¹⁸F-HTK01146) for B1R PET imaging. Peptides were synthesized via solid phase strategy. Nonradioactive standards were obtain by reacting GaCl₃ with DOTA-dPEG2-R954 and by clicking N-propargyl-N,N-dimethylammoniomethyl-trifluoroborate with azidoacetyl-dPEG2-R954. Binding affinity for B1R was determined by an in vitro competition binding assay. ⁶⁸Ga-HTK01083 was obtained by incubating DOTA-dPEG2-R954 with ⁶⁸GaCl₃ under acidic conditions, while ¹⁸F-HTK01146 was prepared via an ¹⁸F–¹⁹F isotope exchange reaction. Biodistribution and imaging studies were conducted at 1 h postinjection (p.i.) in mice inoculated with B1R-expressing (B1R+) and B1R-nonexpressing (B1R−) cells. HTK01083 and HTK01146 bound B1R with good affinity (K_i = 30.5 and 24.8 nM, respectively). ⁶⁸Ga/¹⁸F-labeled R954 were obtained on average in ≥10% decay-corrected radiochemical yield with >99% radiochemical purity and ≥52 GBq/μmol specific activity. For both tracers, clearance was predominantly renal with minimal involvement of the hepatobiliary system. For PET images, B1R+ tumors, kidneys, and bladder were visible. At 1 h p.i., uptake in B1R+ tumor was comparable between ⁶⁸Ga-HTK01083 (8.46 ± 1.44%ID/g) and ¹⁸F-HTK01146 (9.25 ± 0.69%ID/g). B1R+ tumor-to-blood and B1R+ tumor-to-muscle ratios were 6.32 ± 1.44 and 20.7 ± 3.58 for ⁶⁸Ga-HTK01083, and 7.24 ± 2.56 and 19.5 ± 4.29 for ¹⁸F-HTK01146. Our results indicate R954 is a good lead sequence for optimization of B1R tracers for cancer imaging.

中文翻译：

正电子发射断层显像成像缓激肽B1受体表达的放射性标记的R954衍生物

肽受体已经成为诊断和治疗的有希望的靶标。这些受体在不同癌症亚型中的异常过表达允许采用补充常规化学疗法的新治疗策略。缓激肽B1受体（B1R）是一种G蛋白偶联受体，在许多癌症中均过表达，在健康组织中的表达有限。以前，我们开发了B1R拮抗剂肽B9858和B9958的⁶⁸ Ga和¹⁸ F标记的衍生物，并成功地靶向体内表达B1R的肿瘤异种移植物。R954（Ac-Orn-Arg-Oic-Pro-Gly-αMePhe-Ser- d -2-Nal-Ile）是有效的B1R拮抗剂，据报道它对肽酶降解的稳定性比B9858稳定。我们评估了R954的两种放射性标记的衍生物（⁶⁸ Ga-HTK01083和¹⁸ F-HTK01146）用于B1R PET成像。通过固相策略合成肽。通过使GaCl ₃与DOTA-dPEG2-R954反应并通过单击N-炔丙基-N，N-二甲基氨甲基-三氟硼酸酯与叠氮基乙酰基-dPEG2-R954来获得非放射性标样。通过体外竞争结合试验确定对B1R的结合亲和力。通过在酸性条件下将DOTA-dPEG2-R954与⁶⁸ GaCl ₃孵育获得⁶⁸ Ga-HTK01083 ，而通过¹⁸ F– ¹⁹制备¹⁸ F-HTK01146F同位素交换反应。在注射后1 h（pi）接种了表达B1R（B1R +）和不表达B1R（B1R-）的小鼠中进行了生物分布和成像研究。HTK01083和HTK01146以良好的亲和力结合B1R（分别为K _i = 30.5和24.8 nM）。平均获得⁶⁸ Ga / ¹⁸ F标记的R954，其衰变校正放射化学产率≥10％，放射化学纯度> 99％，比活度≥52GBq /μmol。对于这两种示踪剂，清除率主要为肾脏，肝胆系统受累最小。对于PET图像，可见B1R +肿瘤，肾脏和膀胱。感染后1小时，B1R +肿瘤的摄取在⁶⁸ Ga-HTK01083（8.46±1.44％ID / g）和^18之间F-HTK01146（9.25±0.69％ID / g）。对于⁶⁸ Ga-HTK01083，B1R +肿瘤与血液的比率和B1R +肿瘤与肌肉的比率为6.32±1.44和20.7±3.58，对于¹⁸ F-HTK01146为7.24±2.56和19.5±4.29 。我们的结果表明，R954是用于癌症成像的B1R示踪剂优化的良好先导序列。

更新日期：2017-02-02

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