Radiolabeled B9958 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography: Effect of the Radiolabel–Chelator Complex on Biodistribution and Tumor Uptake

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• 作者：Zhengxing Zhang ; Guillaume Amouroux ; Jinhe Pan ; Silvia Jenni ; Jutta Zeisler ; Chengcheng Zhang ; Zhibo Liu ; David M. Perrin ; François Bénard ; Kuo-Shyan Lin
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：August 1, 2016
• 年：2016
• 卷：13
• 期：8
• 页码：2823-2832
• 全文大小：389K
• 年卷期：0
• ISSN：1543-8392

文摘

Bradykinin B1 receptor (B1R), which is upregulated in a variety of malignancies, is an attractive cancer imaging biomarker. In this study we optimized the selection of radiolabel–chelator complex to improve tumor uptake and tumor-to-background contrast of radiolabeled analogues of B9958 (Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-pan class="smallcaps">dpan>-Tic-Cpg), a potent B1R antagonist. Peptide sequences were assembled on solid phase. Cold standards were prepared by incubating DOTA-/NODA-conjugated peptides with GaCl₃, and by incubating AlOH-NODA-conjugated peptide with NaF. Binding affinities were measured via in vitro competition binding assays. ⁶⁸Ga and ¹⁸F labeling experiments were performed in acidic buffer and purified by HPLC. Imaging/biodistribution studies were performed in mice bearing both B1R-positive (B1R+) HEK293T::hB1R and B1R-negative (B1R−) HEK293T tumors. Z02176 (Ga-DOTA-Pip-B9958; Pip: 4-amino-(1-carboxymethyl)piperidine), Z02137 (Ga-NODA-Mpaa-Pip-B9958; Mpaa: 4-methylphenylacetic acid), and Z04139 (AlF-NODA-Mpaa-Pip-B9958) bound hB1R with high affinity (K_i = 1.4–2.5 nM). ⁶⁸Ga-/¹⁸F-labeled peptides were obtained on average in ≥32% decay-corrected radiochemical yield with >99% radiochemical purity and 100–261 GBq/μmol specific activity. Biodistribution/imaging studies at 1 h postinjection showed that all tracers cleared rapidly from background tissues (except kidneys) and were excreted predominantly via the renal pathway. Only kidneys, bladders, and B1R+ tumors were clearly visualized in PET images. Uptake in B1R+ tumor was higher by using ⁶⁸Ga-Z02176 (28.9 ± 6.21 %ID/g) and ¹⁸F-Z04139 (22.6 ± 3.41 %ID/g) than ⁶⁸Ga-Z02137 (14.0 ± 4.86 %ID/g). The B1R+ tumor-to-blood and B1R+ tumor-to-muscle contrast ratios were also higher for ⁶⁸Ga-Z02176 (56.1 ± 17.3 and 167 ± 57.6) and ¹⁸F-Z04139 (58.0 ± 20.9 and 173 ± 42.9) than ⁶⁸Ga-Z02137 (34.3 ± 15.2 and 103 ± 30.2). With improved target-to-background contrast ⁶⁸Ga-Z02176 and ¹⁸F-Z04139 are promising for imaging B1R expression in cancers with PET.