European Journal of Nuclear Medicine and Molecular Imaging Vol. 31, No. 8, August 2004 European Journal of Nuclear Medicine and Molecular Imaging Vol. 30, No. 1, January 2003 Abstract. We have previously labeled cyclic RGD pep- tide c(RGDyK) with fluorine-18 through conjugation labeling via a prosthetic 4-[ 18 F]fluorobenzoyl moiety and applied this [ 18 F]FB-RGD radiotracer for α v -integrin ex- pression 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 [ 18 F]FB-RGD tracer by inserting a heterobifunctional poly(ethylene glycol) (PEG, M.W. =3,400) between the 18 F radiolabel and the RGD moiety and to test this [ 18 F]FB-PEG-RGD tracer for brain tumor targeting and in vivo kinetics. [ 18 F]FB-PEG-RGD was prepared by coupling the RGD-PEG conjugate with N-succinimidyl 4-[ 18 F]fluorobenzoate ([ 18 F]SFB) under slightly basic conditions (pH=8.5). The radiochemical yield was about 20–30% based on the active ester [ 18 F]SFB, and specific activity was over 100 GBq/μmol. This tracer had fast blood clearance, rapid and high tumor uptake in the sub- cutaneous U87MG glioblastoma model (5.2±0.5%ID/g at 30 min p.i.). Moderately rapid tumor washout was ob- served, 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 [ 18 F]FB-PEG- RGD. Although uptake in the orthotopic tumor was sig- nificantly lower (P<0.01) than in the subcutaneous tu- mor, 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 im- aging. In conclusion, PEGylation suitably modifies the physiological behavior of the RGD peptide. [ 18 F]FB- PEG-RGD gave improved tumor retention and in vivo kinetics compared with [ 18 F]FB-RGD. Keywords: Angiogenesis – Integrin – RGD – PEGyla- tion – MicroPET Eur J Nucl Med Mol Imaging (2004) 31:1081–1089 DOI 10.1007/s00259-003-1452-2 Introduction Although brain tumors are not the most common type of neoplasms, they are among the most devastating cancers [1]. Most brain tumors are relatively insensitive to tradi- tional radiation and chemotherapy due to the fact that the drugs either do not cross the blood-brain barrier (BBB) in the brain adjacent to the tumor or do not cross the blood-tumor barrier in an adequate amount to elicit the desired response [2]. Marked progress in molecular and cellular biology is enabling rapid identification of molec- ular targets and subsequently the development of novel targeted therapies that are less toxic and more effective than existing therapies [2, 3]. Current positron emission tomography (PET) imaging of brain tumors using either metabolic radiotracers (such as FDG) [4] or cell prolifer- ation markers (such as FLT and FMAU) [5, 6] do not take advantage of the specific targeting that these new therapies offer. Angiogenesis, the formation of new blood vessels from the preexisting vasculature, plays a critical role in tumor growth and metastasis [7]. Antiangiogenic thera- pies that aim to restore endothelial cells to their normal state and prevent the vessels from nourishing tumors, thereby arresting the cancer, possess a number of advan- tages over conventional chemotherapies that target tumor Peter S. Conti ( ✉ ) 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 e-mail: pconti@usc.edu Tel.: +1-323-4425940, Fax: +1-323-4423253 Original article MicroPET imaging of brain tumor angiogenesis with 18 F-labeled PEGylated RGD peptide Xiaoyuan Chen 1 , Ryan Park 1 , Yingping Hou 1 , Vazgen Khankaldyyan 2 , Ignacio Gonzales-Gomez 2 , Michel Tohme 1 , James R. Bading 1 , Walter E. Laug 2 , Peter S. Conti 1 1 PET Imaging Science Center, Department of Radiology, University of Southern California Keck School of Medicine, Los Angeles, USA 2 Department of Pediatrics, Childrens Hospital Los Angeles, Los Angeles, USA Received: 3 November 2003 / Accepted: 19 December 2003 / Published online: 29 April 2004 © Springer-Verlag 2004