Facile synthesis and ¹⁸F-radiolabeling of α₄β₁-specific LLP2A-aryltrifluoroborate peptidomimetic conjugates

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• 作者：Daniel Walker^a ; Ying Li^a ; Á ; ron Roxin^a ; Paul Schaffer^b ; Michael J. Adam^b ; David M. Perrin^a ; ^{dperrin@chem.ubc.ca" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Peptidomimetic ; Radiotracer ; Integrin receptor ; F-18
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 October 2016
• 年：2016
• 卷：26
• 期：20
• 页码：5126-5131
• 全文大小：981 K

文摘

The peptidomimetic, LLP2A, is a specific, high-affinity ligand for α₄β₁ integrin receptors. Previously, several PEGylated LLP2A conjugates were evaluated in vivo as imaging agents for the detection of lymphoma, leukemia, multiple myeloma and melanoma tumours via NIR-fluorescence, ¹¹¹In-SPECT, and ⁶⁴Cu- and ⁶⁸Ga-PET imaging. Despite these successes, to date there is no report of an ¹⁸F-labeled LLP2A conjugate. Notably, fluorine-18 is a preferred radionuclide for PET imaging, yet its short half-life and general inactivity under aqueous conditions present challenges for peptide labeling. A simple method for labeling complex biomolecules can be achieved with arylboronic acids that readily capture aqueous [¹⁸F]-fluoride ion resulting in an ¹⁸F-labeled aryltrifluoroborate ([¹⁸F]-ArBF₃⁻) radioprosthetic group. Herein, we present the first radiosynthesis of an ¹⁸F-labeled LLP2A conjugate by both one-step ¹⁸F‐labeling and one-pot two-step ¹⁸F-labeling post-‘click’ conjugation of the ¹⁸F-alkynyl-ArBF₃⁻ prosthetic. Competition with a fluorescent conjugate of LLP2A demonstrated specific binding of the non-radioactive isotopolog ArBF₃⁻-PEG₂-LLP2A to α₄β₁ integrin-expressing MOLT-4 leukemia cells, as evidenced and confirmed by fluorescence microscopy. This work provides a key first step in the development of an expanding library of [¹⁸F]-R-BF₃⁻-LLP2A radiotracers for PET imaging.