Triazine-Based Tool Box for Developing Peptidic PET Imaging Probes: Syntheses, Microfluidic Radiolabeling, and Structure鈥揂ctivity Evaluation

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• 作者：Hairong Li ; Haiying Zhou ; Stephanie Krieger ; Jesse J. Parry ; Joseph J. Whittenberg ; Amit V. Desai ; Buck E. Rogers ; Paul J. A. Kenis ; David E. Reichert
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：April 16, 2014
• 年：2014
• 卷：25
• 期：4
• 页码：761-772
• 全文大小：421K
• 年卷期：v.25,no.4(April 16, 2014)
• ISSN：1520-4812

文摘

This study was aimed at developing a triazine-based modular platform for targeted PET imaging. We synthesized mono- or bis-cyclo(RGDfK) linked triazine-based conjugates specifically targeting integrin 伪_v尾₃ receptors. The core molecules could be easily linked to targeting peptide and radiolabeled bifunctional chelator. The spacer core molecule was synthesized in 2 or 3 steps in 64鈥?0% yield, and the following conjugation reactions with cyclo(RGDfK) peptide or bifunctional chelator were accomplished using 鈥渃lick鈥?chemistry or amidation reactions. The DOTA-TZ-Bis-cyclo(RGDfK) 13 conjugate was radiolabeled successfully with ⁶⁴Cu(OAc)₂ using a microfluidic method, resulting in higher specific activity with above 95% labeling yields compared to conventional radiolabeling (SA ca. 850 vs 600 Ci/mmol). The dimeric cyclo(RGDfK) peptide was found to display significant bivalency effect using I¹²⁵-Echistatin binding assay with IC₅₀ value as 178.5 卤 57.1 nM, which displayed a 3.6-fold enhancement of binding affinity compared to DOTA-TZ-cyclo(RGDfK) 14 conjugate on U87MG human glioblastoma cell. Biodistribution of all four conjugates in female athymic nude mice were evaluated. DOTA-鈥淐lick鈥?cyclo(RGDfK) 15 had the highest tumor uptake among these four at 4 h p.i. with 1.90 卤 0.65%ID/g, while there was no clear bivalency effect for DOTA-TZ-BisRGD in vivo, which needs further experiments to address the unexpected questions.