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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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[18F]Fluorobenzoyl-((VHPKQHRGGSY)2K)2KK

[18F]4V
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: September 30, 2010.

Chemical name:[18F]Fluorobenzoyl-((VHPKQHRGGSY)2K)2KK
Abbreviated name:[18F]4V
Synonym:
Agent category:Peptide
Target:Vascular cell adhesion molecule-1 (VCAM-1)
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:18F
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about VCAM-1.

Background

[PubMed]

Endothelial cells are important cells in inflammatory responses (1-2). Bacterial lipopolysaccharide, virus, inflammation, and tissue injury increase secretion of tumor necrosis factor α (TNFα), interleukin-1 (IL-1), and other cytokines and chemokines. Emigration of leukocytes from blood is dependent on their ability to adhere to endothelial cell surfaces. Inflammatory mediators and cytokines induce chemokine secretion from endothelial cells and other vascular cells and increase their expression of cell surface adhesion molecules, such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), integrins, and selectins. Chemokines are chemotactic toward leukocytes and toward sites of inflammation and tissue injury. The movements of leukocytes through endothelial junctions into the extravascular space are highly orchestrated through various interactions with different adhesion molecules on endothelial cells (3).

VCAM-1 is found in very low amounts on the cell surface of resting endothelial cells and other vascular cells, such as smooth muscle cells and fibroblasts (4-8). VCAM-1 binds to the very late antigen-4 (VLA-4) integrin on the cell surface of leukocytes. IL-1 and TNFα increase expression of VCAM-1 and other cell adhesion molecules on the vascular endothelial cells, which leads to leukocyte adhesion to the activated endothelium. Furthermore, VCAM-1 expression is also induced by oxidized low-density lipoproteins under atherogenic conditions (9). Overexpression of VCAM-1 by atherosclerotic lesions plays an important role in their progression to vulnerable plaques, which may erode and rupture. Cross-linked iron oxide nanoparticles targeted with anti-VCAM-1 antibody are being developed as a noninvasive agent for VCAM-1 expression in vascular endothelial cells during different stages of inflammation in atherosclerosis (10). A tetrameric linear peptide, ((VHPKQHRGGSY)2K)2KK (TLP), was identified with phage screening against VCAM-1 and radiolabeled with 4-[18F]fluorobenzaldehyde ([18F]FBA) to form [18F]fluorobenzoyl-TLP ([18F]4V) as a potential positron emission tomography (PET) imaging agent to target atherosclerotic plaques and myocardial ischemic lesions (11).

Synthesis

[PubMed]

Nahrendorf et al. (11) reported the synthesis of [18F]4V. The tetrameric linear peptide, TLP, was synthesized using standard Fmoc chemistry on an amide resin with a peptide synthesizer. TLP was then reacted with [18F]FBA to form [18F]4V using an automated synthesizer. [18F]4V was purified with high-performance liquid chromatography. The specific activity, radiochemical purity, radiolabeling yield, and total time of synthesis of [18F]4V were not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Nahrendorf et al. (11) measured the binding affinity of TLP to human VCAM-1 with a 50% inhibition concentration (IC50) value of 87 nM (349-fold better than the linear monomer) using 99mTc-DOTA-TLP as a ligand tracer. The accumulation of [18F]4V (100 ng) in murine heart endothelial cells in culture was inhibited by >95% with 1 µg murine soluble VCAM-1. Incubation of [18F]4V with excised aortas from wild-type mice, apoE-/- mice, and apoE-/- mice treated with atorvastatin showed that aortas from apoE-/- mice exhibited >2-fold higher radioactivity than the aortas from wild-type mice and apoE-/- mice treated with atorvastatin.

Animal Studies

Rodents

[PubMed]

Nahrendorf et al. (11) performed ex vivo biodistribution studies in wild-type mice (n = 6) at 4 hr after injection. Each mouse received 5.55 MBq (0.15 mCi) [18F]4V. The organ/tissue with the highest accumulation (percent injected dose per gram (% ID/g)) was the kidney (13.2 ± 2.8), followed by the liver (3.7 ± 1.1), lymph node (3.7 ± 0.3), lung (2.2 ± 0.8), spleen (2.1 ± 0.6), small intestine (1.9 ± 0.4), skin (1.7 ± 0.6), stomach (1.7 ± 1.1), blood (1.5 ± 0.4), large intestine (1.4 ± 0.5), aorta (1.3 ± 0.4), bone (1.3 ± 0.4), skeletal muscle (0.7 ± 0.3), heart (0.6 ± 0.2), and feces (0.2 ± 0.1). Dynamic PET/CT imaging of apoE-/- mice (n = 8) was conducted with intravenous injection of 13 MBq (0.35 mCi) [18F]4V for 7 h. Strong focal signal in the aortic root was identified at 1–2 h with an aorta/blood ratio of 2. Atorvastatin treatment blocked the signal increase to near the signal expression of the wild-type aortas (P < 0.05). [18F]4V radioactivity correlated with VCAM-1 mRNA levels (R = 0.79, P = 0.03) in the excised aortas.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

NIH Support

R01 HL078641, R24 CA092782, U01 HL080731

References

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Cybulsky M.I., Gimbrone M.A. Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1991;251(4995):788–91. [PubMed: 1990440]
2.
Lowe J.B. Glycosylation in the control of selectin counter-receptor structure and function. Immunol Rev. 2002;186:19–36. [PubMed: 12234359]
3.
Vanderslice P., Woodside D.G. Integrin antagonists as therapeutics for inflammatory diseases. Expert Opin Investig Drugs. 2006;15(10):1235–55. [PubMed: 16989599]
4.
Bochner B.S., Luscinskas F.W., Gimbrone M.A. Jr, Newman W., Sterbinsky S.A., Derse-Anthony C.P., Klunk D., Schleimer R.P. Adhesion of human basophils, eosinophils, and neutrophils to interleukin 1-activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules. J Exp Med. 1991;173(6):1553–7. [PMC free article: PMC2190849] [PubMed: 1709678]
5.
Kume N., Cybulsky M.I., Gimbrone M.A. Jr. Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest. 1992;90(3):1138–44. [PMC free article: PMC329976] [PubMed: 1381720]
6.
Leung K.H. Release of soluble ICAM-1 from human lung fibroblasts, aortic smooth muscle cells, dermal microvascular endothelial cells, bronchial epithelial cells, and keratinocytes. Biochem Biophys Res Commun. 1999;260(3):734–9. [PubMed: 10403835]
7.
Luscinskas F.W., Cybulsky M.I., Kiely J.M., Peckins C.S., Davis V.M., Gimbrone M.A. Jr. Cytokine-activated human endothelial monolayers support enhanced neutrophil transmigration via a mechanism involving both endothelial-leukocyte adhesion molecule-1 and intercellular adhesion molecule-1. J Immunol. 1991;146(5):1617–25. [PubMed: 1704400]
8.
Nagel T., Resnick N., Atkinson W.J., Dewey C.F. Jr, Gimbrone M.A. Jr. Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells. J Clin Invest. 1994;94(2):885–91. [PMC free article: PMC296171] [PubMed: 7518844]
9.
Aikawa M., Libby P. The vulnerable atherosclerotic plaque: pathogenesis and therapeutic approach. Cardiovasc Pathol. 2004;13(3):125–38. [PubMed: 15081469]
10.
Tsourkas A., Shinde-Patil V.R., Kelly K.A., Patel P., Wolley A., Allport J.R., Weissleder R. In vivo imaging of activated endothelium using an anti-VCAM-1 magnetooptical probe. Bioconjug Chem. 2005;16(3):576–81. [PubMed: 15898724]
11.
Nahrendorf M., Keliher E., Panizzi P., Zhang H., Hembrador S., Figueiredo J.L., Aikawa E., Kelly K., Libby P., Weissleder R. 18F-4V for PET-CT imaging of VCAM-1 expression in atherosclerosis. JACC Cardiovasc Imaging. 2009;2(10):1213–22. [PMC free article: PMC2773129] [PubMed: 19833312]

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