AMD3100: A Versatile Platform for CXCR4 Targeting 68Ga-Based Radiopharmaceuticals

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• 作者：Sophie Poty ; Eleni Gourni ; Pauline Désogère ; Frédéric Boschetti ; Christine Goze ; Helmut R. Maecke ; Franck Denat
• 刊名：Bioconjugate Chemistry
• 出版年：2016
• 出版时间：March 16, 2016
• 年：2016
• 卷：27
• 期：3
• 页码：752-761
• 全文大小：427K
• ISSN：1520-4812

文摘

CXCR4 is a G protein-coupled receptor (GPCR), which is overexpressed in numerous diseases, particularly in multiple cancers. Therefore, this receptor represents a valuable target for imaging and therapeutic purposes. Among the different approaches, which were developed for CXCR4 imaging, a CXCR4 antagonist biscyclam system (AMD3100, also called Mozobil), currently used in the clinic for the mobilization of hematopoietic stem cells, was radiolabeled with different radiometals such as ⁶²Zn, ⁶⁴Cu, ⁶⁷Ga, or ^99mTc. However, cyclam is not an ideal chelator for most of these radiometals, and could lead to the release of the radionuclide in vivo. In the current study, a new family of CXCR4 imaging agents is presented, in which AMD3100 is used as a carrier for specific delivery of an imaging reporter, i.e., a ⁶⁸Ga complex for PET imaging. AMD3100 was functionalized on the phenyl moiety with different linkers, either ethylenediamine or diamino-polyethylene glycol 3 (PEG₃). The resulting AMD3100 analogues were further coupled with two different chelators, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid (NODAGA). Five potential CXCR4 targeting agents were obtained. The derived AMD3100-based ligands were labeled with ⁶⁸Ga, highlighting the influence of the spacer nature on the ⁶⁸Ga-labeling yield. The lipophilic character of the different systems was also investigated, as well as their affinity for the CXCR4 receptor. The most promising compound was further evaluated in vivo in H69 tumor xenografts by biodistribution and PET imaging studies, validating the proof of principle of our concept.