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Triazine-based tool box for developing peptidic PET imaging probes: syntheses, microfluidic radiolabeling, and
Hairong Li1, Haiying Zhou, Stephanie Krieger
1Radiological Sciences Division, Mallinckrodt Institute of Radiology, Washington University School of Medicine , 510 South Kingshighway Boulevard, St. Louis, Missouri 63110, United States.
Bioconjugate Chemistry
|March 26, 2014
Summary
This study presents a new triazine platform for targeted PET imaging, creating RGD-peptide conjugates that bind to integrin αvβ3 receptors. The developed method shows high radiolabeling efficiency and potential for glioblastoma imaging.
Area of Science:
- Radiochemistry
- Molecular Imaging
- Medicinal Chemistry
Background:
- Targeted positron emission tomography (PET) imaging requires specific molecular probes to detect disease biomarkers.
- Integrin αvβ3 receptors are overexpressed in various cancers, making them attractive targets for imaging and therapy.
- Developing modular and efficient platforms for synthesizing targeted radiotracers is crucial for advancing molecular imaging.
Purpose of the Study:
- To develop a versatile triazine-based modular platform for creating targeted PET imaging agents.
- To synthesize and characterize novel mono- and bis-cyclo(RGDfK) linked triazine conjugates for integrin αvβ3 receptor targeting.
- To evaluate the radiolabeling efficiency, binding affinity, and in vivo performance of these conjugates.
Main Methods:
- Synthesis of triazine-based spacer core molecules.
- Conjugation of cyclo(RGDfK) peptide and bifunctional chelators using click chemistry or amidation.
- Radiolabeling with Copper-64 (64Cu) using microfluidic and conventional methods.
- In vitro binding assays (e.g., I(125)-Echistatin binding) and cell-based studies (U87MG glioblastoma cells).
- In vivo biodistribution studies in female athymic nude mice.
Main Results:
- The triazine core molecule was synthesized in 2-3 steps with high yields (64-80%).
- Successful radiolabeling of DOTA-TZ-Bis-cyclo(RGDfK) conjugate with 64Cu achieved >95% yield and higher specific activity via microfluidics.
- Dimeric cyclo(RGDfK) peptide showed a 3.6-fold enhancement in binding affinity in vitro due to bivalency.
- DOTA-"Click"-cyclo(RGDfK) exhibited the highest tumor uptake (1.90 ± 0.65%ID/g at 4h p.i.) in mice.
- No clear bivalency effect was observed in vivo, warranting further investigation.
Conclusions:
- The triazine-based platform offers a modular and efficient approach for developing targeted PET imaging agents.
- Microfluidic radiolabeling significantly improves specific activity and labeling yield.
- While in vitro studies suggest a bivalency advantage, in vivo results require further exploration to understand the discrepancy.
- These RGD-triazine conjugates show promise for integrin αvβ3-targeted PET imaging, particularly for glioblastoma.
