Triazine-based tool box for developing peptidic PET imaging probes: Syntheses, microfluidic radiolabeling, and structure-activity evaluation

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

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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 α vÎ3 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 64-80% yield, and the following conjugation reactions with cyclo(RGDfK) peptide or bifunctional chelator were accomplished using “clickâ€? 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 ± 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-“Clickâ€?-cyclo(RGDfK) 15 had the highest tumor uptake among these four at 4 h p.i. with 1.90 ± 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.

Original languageEnglish
Pages (from-to)761-772
Number of pages12
JournalBioconjugate Chemistry
Volume25
Issue number4
DOIs
StatePublished - Apr 16 2014

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