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MicroPET imaging of brain tumor angiogenesis with 18F-labeled PEGylated RGD peptide

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Abstract

We have previously labeled cyclic RGD peptide c(RGDyK) with fluorine-18 through conjugation labeling via a prosthetic 4-[18F]fluorobenzoyl moiety and applied this [18F]FB-RGD radiotracer for αv-integrin expression imaging in different preclinical tumor models with good tumor-to-background contrast. However, the unfavorable hepatobiliary excretion and rapid tumor washout rate of this tracer limit its potential clinical applications. The aims of this study were to modify the [18F]FB-RGD tracer by inserting a heterobifunctional poly(ethylene glycol) (PEG, M.W. =3,400) between the 18F radiolabel and the RGD moiety and to test this [18F]FB-PEG-RGD tracer for brain tumor targeting and in vivo kinetics. [18F]FB-PEG-RGD was prepared by coupling the RGD-PEG conjugate with N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) under slightly basic conditions (pH=8.5). The radiochemical yield was about 20–30% based on the active ester [18F]SFB, and specific activity was over 100 GBq/μmol. This tracer had fast blood clearance, rapid and high tumor uptake in the subcutaneous U87MG glioblastoma model (5.2±0.5%ID/g at 30 min p.i.). Moderately rapid tumor washout was observed, with the activity accumulation decreased to 2.2±0.4%ID/g at 4 h p.i. MicroPET and autoradiography imaging showed a very high tumor-to-background ratio and limited activity accumulation in the liver, kidneys and intestinal tracts. U87MG tumor implanted into the mouse forebrain was well visualized with [18F]FB-PEG-RGD. Although uptake in the orthotopic tumor was significantly lower (P<0.01) than in the subcutaneous tumor, the maximum tumor-to-brain ratio still reached 5.0±0.6 due to low normal brain background. The results of H&E staining post mortem agreed with the anatomical information obtained from non-invasive microPET imaging. In conclusion, PEGylation suitably modifies the physiological behavior of the RGD peptide. [18F]FB-PEG-RGD gave improved tumor retention and in vivo kinetics compared with [18F]FB-RGD.

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Acknowledgements

This work was carried out in part with contributions from ACS grant ACS-IRG-580007-42, the Wright Foundation, NIBIB grant R21 EB001785 and the DOD BCRP Concept Award DAMD17-03-1-0752 (to X.C.), by the T.J. Martell Foundation and R01 Grant CA82989 (to W.E.L.), and by NIH grant P20 CA86532 (to P.S.C.). The USC cyclotron team, particularly Joseph Cook and Luis Pedroza, are acknowledged for radionuclide production.

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Authors and Affiliations

  1. PET Imaging Science Center, Department of Radiology, University of Southern California Keck School of Medicine, 1510 San Pablo St., Suite 350, Los Angeles, CA 90033, USA

    Xiaoyuan Chen, Ryan Park, Yingping Hou, Michel Tohme, James R. Bading & Peter S. Conti

  2. Department of Pediatrics, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA

    Vazgen Khankaldyyan, Ignacio Gonzales-Gomez & Walter E. Laug

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  1. Xiaoyuan Chen
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  2. Ryan Park
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  3. Yingping Hou
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  4. Vazgen Khankaldyyan
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  5. Ignacio Gonzales-Gomez
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  7. James R. Bading
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  8. Walter E. Laug
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  9. Peter S. Conti
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Correspondence to Peter S. Conti.

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Chen, X., Park, R., Hou, Y. et al. MicroPET imaging of brain tumor angiogenesis with 18F-labeled PEGylated RGD peptide. Eur J Nucl Med Mol Imaging 31, 1081–1089 (2004). https://doi.org/10.1007/s00259-003-1452-2

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  • DOI: https://doi.org/10.1007/s00259-003-1452-2

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