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

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 alphav-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/micromol. 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.

• Authors: Xiaoyuan Chen, Ryan Park, Yingping Hou, Vazgen Khankaldyyan, Ignacio Gonzales-Gomez, Michel Tohme, James R Bading, Walter E Laug, Peter S Conti
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 31 Issue 8 Pg. 1081-9 (Aug 2004) ISSN: 1619-7070 [Print] Germany
• PMID: 15118844 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 4-fluorobenzoyl-polyethylene glycol-cyclo(arginyl-glycyl-aspartyl-tyrosyl-lysyl)
• Peptides, Cyclic
• Radiopharmaceuticals
• Polyethylene Glycols

Topics

• Animals
• Brain (blood supply, diagnostic imaging, metabolism)
• Brain Neoplasms (diagnostic imaging, metabolism)
• Female
• Glioblastoma (diagnostic imaging, metabolism)
• Metabolic Clearance Rate
• Mice
• Mice, Nude
• Neovascularization, Pathologic (diagnostic imaging, metabolism)
• Organ Specificity
• Peptides, Cyclic (pharmacokinetics)
• Polyethylene Glycols (pharmacokinetics)
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (pharmacokinetics)
• Tissue Distribution
• Whole-Body Counting