18F-4V for PET-CT Imaging of VCAM-1 Expression in Atherosclerosis

Matthias Nahrendorf, Edmund Keliher, Peter Panizzi, Hanwen Zhang, Sheena Hembrador, Jose Luiz Figueiredo, Elena Aikawa, Kimberly Kelly, Peter Libby, Ralph Weissleder

Research output: Contribution to journalArticlepeer-review

176 Scopus citations

Abstract

Objectives: The aim of this study was to iteratively develop and validate an 18F-labeled small vascular cell adhesion molecule (VCAM)-1 affinity ligand and demonstrate the feasibility of imaging VCAM-1 expression by positron emission tomography-computed tomography (PET-CT) in murine atherosclerotic arteries. Background: Hybrid PET-CT imaging allows simultaneous assessment of atherosclerotic lesion morphology (CT) and may facilitate early risk assessment in individual patients. The early induction, confinement of expression to atherosclerotic lesions, and accessible position in proximity to the blood pool render the adhesion molecule VCAM-1 an attractive imaging biomarker for inflamed atheroma prone to complication. Methods: A cyclic, a linear, and an oligomer affinity peptide, internalized into endothelial cells by VCAM-1-mediated binding, were initially derivatized with DOTA to determine their binding profiles and pharmacokinetics. The lead compound was then 18F-labeled and tested in atherosclerotic apoE-/- mice receiving a high-cholesterol diet as well as wild type murine models of myocardial infarction and heart transplant rejection. Results: The tetrameric peptide had the highest affinity and specificity for VCAM-1 (97% inhibition with soluble VCAM-1 in vitro). In vivo PET-CT imaging using 18F-4V showed 0.31 ± 0.02 SUV in murine atheroma (ex vivo %IDGT 5.9 ± 1.5). 18F-4V uptake colocalized with atherosclerotic plaques on Oil Red O staining and correlated to mRNA levels of VCAM-1 measured by quantitative reverse transcription polymerase chain reaction (R = 0.79, p = 0.03). Atherosclerotic mice receiving an atorvastatin-enriched diet had significantly lower lesional uptake (p < 0.05). Furthermore, 18F-4V imaging in myocardial ischemia after coronary ligation and in transplanted cardiac allografts undergoing rejection showed high in vivo PET signal in inflamed myocardium and good correlation with ex vivo measurement of VCAM-1 mRNA by quantitative polymerase chain reaction. Conclusions: 18F-4V allows noninvasive PET-CT imaging of VCAM-1 in inflammatory atherosclerosis, has the dynamic range to quantify treatment effects, and correlates with inflammatory gene expression.

Original languageEnglish
Pages (from-to)1213-1222
Number of pages10
JournalJACC: Cardiovascular Imaging
Volume2
Issue number10
DOIs
StatePublished - Oct 2009

Keywords

  • PET-CT
  • VCAM-1
  • atherosclerosis
  • inflammation
  • molecular imaging

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