Synthesis and in Vitro and in Vivo Evaluation of SiFA-Tagged Bombesin and RGD Peptides as Tumor Imaging Probes for Positron Emission Tomography

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• 作者：Simon Lindner ; Christina Michler ; Stephanie Leidner ; Christian Rensch ; Carmen W盲ngler ; Ralf Schirrmacher ; Peter Bartenstein ; Bj枚rn W盲ngler
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：April 16, 2014
• 年：2014
• 卷：25
• 期：4
• 页码：738-749
• 全文大小：467K
• 年卷期：v.25,no.4(April 16, 2014)
• ISSN：1520-4812

文摘

Gastrin-releasing-peptide (GRP)-receptors and 伪_v尾₃-integrins are widely discussed as potential target structures for oncological imaging with positron emission tomography (PET). Favored by the overexpression of receptors on the surface of tumor cells good imaging characteristics can be achieved with highly specific radiolabeled receptor ligands. PEGylated bombesin (PESIN) derivatives as specific GRP receptor ligands and RGD (one-letter codes for arginine-glycine-aspartic acid) peptides as specific 伪_v尾₃ binders were synthesized and tagged with a silicon-fluorine-acceptor (SiFA) moiety. The SiFA synthon allows for a fast and highly efficient isotopic exchange reaction at room temperature giving the [¹⁸F]fluoride labeled peptides in up to 62% radiochemical yields (d.c.) and 鈮?9% radiochemical purity in a total synthesis time of less than 20 min. Using nanomolar quantities of precursor high specific activities of up to 60 GBq 渭mol^鈥? were obtained. To compensate the high lipophilicity of the SiFA moiety various hydrophilic structure modifications were introduced leading to significantly reduced logD values. Competitive displacement experiments with the PESIN derivatives showed a 32 to 6 nM affinity to the GRP receptor on PC3 cells, and with the RGD peptides a 7 to 3 渭M affinity to the 伪_v尾₃ integrins on U87MG cells. All derivatives proved to be stable in human plasma over at least 120 min. Small animal PET measurements and biodistribution studies revealed an enhanced and specific accumulation of the RGD peptide ¹⁸F-SiFA-LysMe₃-纬-carboxy-d-Glu-RGD (17) in the tumor tissue of U87MG tumor-bearing mice of 5.3% ID/g whereas the PESIN derivatives showed a high liver uptake and only a low accumulation in the tumor tissue of PC3 xenografts. Stability studies with compound 17 provided further information on its metabolism in vivo. These results altogether demonstrate that the reduction of the overall lipophilicity of SiFA tagged RGD peptides is a promising approach for the generation of novel potent ¹⁸F-labeled imaging agents.