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[18F]Fluorobenzoyl-PEGylated cyclic arginine-glycine-aspartic acid peptide


, PhD and , MD, PhD.

Author Information
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim
, MD, PhD
University of South California, Los Angeles, CA, Corresponding Author, ude.csu@itnocp

Created: ; Last Update: July 4, 2008.

Chemical name:[18F]Fluorobenzoyl-PEGylated cyclic arginine-glycine-aspartic acid peptideimage 24877527 in the ncbi pubchem database
Abbreviated name:[18F]FB-PEG-c(RGDyK)
Agent Category:Peptide
Target:Integrin αvβ3
Target Category:Receptor binding
Method of detection:Positron Emission Tomography (PET)
Source of signal/contrast:18F
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Click on the above structure for additional information in PubChem.
Click on protein, nucleotide (RefSeq), and gene for more information about integrin αvβ3.



[18F]Fluorobenzoyl-PEGylated cyclic arginine-glycine-aspartic acid peptide ([18F]FB-PEG-c(RGDyK)) is an integrin-targeted molecular imaging agent developed for positron emission tomography (PET) of tumor vasculature and angiogenesis (1). 18F is a positron emitter with a physical half-life (t½) of 110 min.

Cellular survival, invasion, and migration control embryonic development, angiogenesis, tumor metastasis, and other physiologic processes (2, 3). Among the molecules that regulate angiogenesis are integrins, which comprise a superfamily of cell adhesion proteins that form heterodimeric receptors for extracellular matrix (ECM) molecules (4, 5). These transmembrane glycoproteins consist of two noncovalently associated subunits, α and β (18 α- and 8 β-subunits in mammals), which are assembled into at least 24 α/β pairs. Several integrins, such as integrin αvβ3, have affinity for the arginine-glycine-aspartic acid (RGD) tripeptide motif, which is found in many ECM proteins. Expression of integrin αvβ3 receptors on endothelial cells is stimulated by angiogenic factors and environments. The integrin αvβ3 receptor is generally not found in normal tissue, but it is strongly expressed in vessels with increased angiogenesis, such as tumor vasculature. It is significantly upregulated in certain types of tumor cells and in almost all tumor vasculature.

Molecular imaging probes carrying the RGD motif that binds to the integrin αvβ3 can be used to image tumor vasculature and evaluate angiogenic response to tumor therapy (6, 7). Various RGD peptides in both linear and cyclic forms (RGDfK or RGDyK) have been developed for in vivo binding to integrin αvβ3 (8). Chen et al. (9) evaluated a cyclic RGD D-Tyr analog peptide [c(RGDyK)] labeled with 64Cu or 18F in nude mice bearing a breast tumor. [18F]FB-c(RGDyK) showed high tumor accumulation but also rapid tumor washout with unfavorable biliary excretion (10). To improve the pharmacokinetics and tumor retention of the radiolabeled peptide, a dimer analog was synthesized as [18F]FB-[c(RGDyK)]2, which showed improved tumor localization and predominant renal excretion (11). Alternatively, Chen et al. (12) modified c(RGDyK) with monofunctional methoxy-polyethylene glycol (mPEG; molecular weight = 2,000 kDa) and showed that the modified PEGylated RGD peptide had faster blood clearance, lower kidney uptake, and prolonged tumor uptake. Using the same strategy, Chen et al. (1) inserted a heterofunctional PEG (molecular weight = 3,400 kDa) molecule between the [18F]fluorobenzoyl component and the RGD peptide to produce [18F]FB-PEG-c(RGDyK) for imaging of brain tumor angiogenesis. The PEGylated [18F]FB-c(RGDyK) analog appeared to improve tumor retention and in vivo kinetics compared with [18F]FB-c(RGDyK). These improvements might be attributed to a number of possible causes that include shielding of antigenic and immunogenic epitopes, shielding receptor-mediated uptake by the reticuloendothelial systems, preventing the recognition and degradation by proteolytic enzymes, and increasing the apparent size of the peptide.



Chen et al. (1) reported the synthesis of [18F]FB-PEG-c(RGDyK). The c(RGDyK) peptide was first prepared via solution cyclization of the fully protected linear pentapeptide H-Gly-Asp(OtBu)-D-Tyr(OtBu)-Lys(Boc)-Arg(Pbf)-OH, followed by deprotection with trifluoroacetic acid (TFA) in the presence of the free radical scavenger triisopropylsilane (12). The NH2-PEG-c(RGDyK)-PEG conjugate was prepared by coupling of c(RGDyK) with tert-butoxycarbonyl (t-Boc)-protected PEG-succinimidyl ester (t-Boc-NH-PEG-CO2Su). The active succinimidyl ester was reacted with the є-amino group of the Lys side chain at pH 8.5, which led to the formation of a stable amide linkage with a 70% yield. The t-Boc protecting group was unblocked by TFA cleavage to produce the NH2-PEG-c(RGDyk) conjugate with a 70% yield. The conjugate was then purified by semipreparative high-performance liquid chromatography (HPLC). The molecular weight of the PEG-c(RGDyK) conjugate was determined to be ~4,300 by mass spectrometry, which is in agreement with the theoretical value.

The purified product of NH2-PEG-c(RGDyk) was labeled with 18F by coupling with N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) (1, 10). [18F]SFB was prepared by reacting the 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[8.8.8]hexacosan (K222)+/18F complex with ethyl 4-trimethylammoniumbenzoate trifluoromethane-sulfonate, followed by hydrolyzation with 0.1 M sodium hydroxide and then reacting the solution with tetrafluoroborate. The (K222)+/18F complex was obtained by combining K222 with [18F]F produced via the 19O(p,n)18F reaction. The specific activity of [18F]SFB was 200–250 GBq/μmol (5.4–6.8 Ci/μmol) at the end of synthesis or 300–400 GBq/μmol (8.1−10.8 Ci/μmol) at the end of bombardment. The radiolabeling was performed by mixing [18F]SFB with 1 mg (0.25 μmol) of NH2-PEG-c(RGDyk) in a phosphate buffer (pH 8.5) at 45ºC for 45 min until most of the [18F]SFB had reacted with the lysine є-amino group. The final product was purified by HPLC. The decay-corrected yield of [18F]FB-PEG-c(RGDyK) ranged from 20–30% (n = 4). The radiochemical purity was >99%. The specific activity of the labeled peptide was estimated to be >100 GBq/μmol (2.7 Ci/μmol) on the basis of [18F]SFB activity. The dose used for microPET imaging contained 7.4 MBq/200 ng (200 μCi/200 ng) of RGD-PEG conjugate at the time of injection.

In Vitro Studies: Testing in Cells and Tissues


No publication is currently available.

Animal Studies



Biodistribution studies of [18F]FB-PEG-c(RGDyK) were conducted in nude mice bearing s.c. U87MG glioblastoma (0.4–0.6 cm in diameter) (1). Each mouse received ~740 kBq (20 μCi) of [18F]FB-PEG-c(RGDyK) by i.v. administration. The radioligand was rapidly cleared from the blood and most organs, and the kidneys appeared to be the major route of excretion. The radioactivity levels (n = 4) in percent injected dose per g (% ID/g) in the tumor were 5.19 ± 0.47 (0.5 h), 2.89 ± 0.20 (1 h), 2.56 ± 0.12 (2 h), and 2.15 ± 0.40 (4 h). The blood radioactivity levels were 1.24 ± 0.12 (0.5 h), 0.33 ± 0.18 (1 h), 0.09 ± 0.01 (2 h), and 0.10 ± 0.01 (4 h). The kidney radioactivity levels were 8.14 ± 0.26 (0.5 h), 2.46 ± 0.42 (1 h), 1.75 ± 0.14 (2 h), and 1.44 ± 0.37 (4 h). The liver activity levels were 2.57 ± 0.17 (0.5 h), 1.15 ± 0.13 (1 h), 0.76 ± 0.14 (2 h), and 0.73 ± 0.14 (4 h). When compared with the unPEGylated radioligand, the authors suggested that the PEGylated radioligand appeared to have higher tumor radioactivity levels at all time points and a relatively faster renal clearance. However, no statistical comparison was performed. There was also reduced hepatobiliary excretion and intestinal retention. Coinjection of 10 mg/kg unlabeled c(RGDyK) peptide decreased the radioactivity of [18F]FB-PEG-c(RGDyK) in all tissues except the kidneys. The radioactivity level of the tumor at 1 h was reduced to 0.18 ± 0.03% ID/g.

MicroPET imaging of 7.4 MBq (200 μCi) [18F]FB-PEG-c(RGDyK) in nude mice bearing the s.c. U87MG tumor at 1 h clearly visualized the tumor with a tumor/contralateral background ratio of 8.1 ± 1.2 (1). The gallbladder, urinary bladder, liver, intestines, and kidneys were also visualized. No activity was observed in the normal brain. Using the region-of-interest technique, the radioactivity levels (% ID/g) at 1 h were estimated to be 2.5 ± 0.8 (tumor), 1.1 ± 0.1 (liver), and 2.2 ± 0.2 (kidneys). Digital whole-body autoradiography of the mice after imaging showed a similar radioactivity distribution pattern when compared with that of PET imaging. PET imaging of 7.4 MBq (200 μCi) [18F]FB-PEG-c(RGDyK) in nude mice bearing the intracranially implanted U87MG glioblastoma in the forebrain at 1 h also visualized the tumor with a tumor/brain ratio of 5.0 ± 0.6 (1). The presence and location of the tumor was confirmed by histological staining after the mouse was euthanized at the end of imaging.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


No publication is currently available.

Human Studies


No publication is currently available.


Chen X., Park R., Hou Y., Khankaldyyan V., Gonzales-Gomez I., Tohme M., Bading J.R., Laug W.E., Conti P.S. MicroPET imaging of brain tumor angiogenesis with 18F-labeled PEGylated RGD peptide. Eur J Nucl Med Mol Imaging. 2004;31(8):1081–9. [PubMed: 15118844]
Jin H., Varner J. Integrins: roles in cancer development and as treatment targets. Br J Cancer. 2004;90(3):561–5. [PMC free article: PMC2410157] [PubMed: 14760364]
Paulhe F., Manenti S., Ysebaert L., Betous R., Sultan P., Racaud-Sultan C. Integrin function and signaling as pharmacological targets in cardiovascular diseases and in cancer. Curr Pharm Des. 2005;11(16):2119–34. [PubMed: 15974963]
Hood J.D., Cheresh D.A. Role of integrins in cell invasion and migration. Nat Rev Cancer. 2002;2(2):91–100. [PubMed: 12635172]
Hwang R., Varner J. The role of integrins in tumor angiogenesis. Hematol Oncol Clin North Am. 2004;18(5):991–1006. [PubMed: 15474331]
Cai W., Shin D.W., Chen K., Gheysens O., Cao Q., Wang S.X., Gambhir S.S., Chen X. Peptide-labeled near-infrared quantum dots for imaging tumor vasculature in living subjects. Nano Lett. 2006;6(4):669–76. [PubMed: 16608262]
Massoud T.F., Gambhir S.S. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 2003;17(5):545–80. [PubMed: 12629038]
Haubner R., Wester H.J. Radiolabeled tracers for imaging of tumor angiogenesis and evaluation of anti-angiogenic therapies. Curr Pharm Des. 2004;10(13):1439–55. [PubMed: 15134568]
Chen X., Park R., Tohme M., Shahinian A.H., Bading J.R., Conti P.S. MicroPET and autoradiographic imaging of breast cancer alpha v-integrin expression using 18F- and 64Cu-labeled RGD peptide. Bioconjug Chem. 2004;15(1):41–9. [PubMed: 14733582]
Chen X., Park R., Shahinian A.H., Tohme M., Khankaldyyan V., Bozorgzadeh M.H., Bading J.R., Moats R., Laug W.E., Conti P.S. 18F-labeled RGD peptide: initial evaluation for imaging brain tumor angiogenesis. Nucl Med Biol. 2004;31(2):179–89. [PubMed: 15013483]
Chen X., Tohme M., Park R., Hou Y., Bading J.R., Conti P.S. Micro-PET imaging of alphavbeta3-integrin expression with 18F-labeled dimeric RGD peptide. Mol Imaging. 2004;3(2):96–104. [PubMed: 15296674]
Chen X., Park R., Shahinian A.H., Bading J.R., Conti P.S. Pharmacokinetics and tumor retention of 125I-labeled RGD peptide are improved by PEGylation. Nucl Med Biol. 2004;31(1):11–9. [PubMed: 14741566]

This MICAD chapter is not included in the Open Access Subset, because it was authored / co-authored by one or more investigators who was not a member of the MICAD staff.

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