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

Bioconjug Chem. 2014 Apr 16;25(4):761-72. doi: 10.1021/bc500034n. Epub 2014 Apr 4.

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 αvβ3 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 "click" chemistry or amidation reactions. The DOTA-TZ-Bis-cyclo(RGDfK) 13 conjugate was radiolabeled successfully with (64)Cu(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 I(125)-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-"Click"-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Click Chemistry
  • Copper Radioisotopes / chemistry
  • Female
  • Glioblastoma / metabolism
  • Humans
  • Integrin alphaVbeta3 / metabolism*
  • Iodine Radioisotopes / chemistry
  • Isotope Labeling
  • Mice
  • Mice, Nude
  • Microfluidic Analytical Techniques
  • Molecular Imaging / methods*
  • Molecular Probes / chemistry*
  • Molecular Probes / metabolism
  • Molecular Probes / pharmacokinetics
  • Molecular Structure
  • Neoplasms, Experimental / metabolism
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / metabolism
  • Peptides, Cyclic / pharmacokinetics
  • Positron-Emission Tomography*
  • Rats
  • Structure-Activity Relationship
  • Tissue Distribution
  • Triazines / chemistry*
  • Triazines / metabolism
  • Triazines / pharmacokinetics
  • Tumor Cells, Cultured

Substances

  • Copper Radioisotopes
  • Integrin alphaVbeta3
  • Iodine Radioisotopes
  • Molecular Probes
  • Peptides, Cyclic
  • Triazines
  • cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl)