This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Nahrendorf, M. Articles by Weissleder, R. PubMed Articles by Nahrendorf, M. Articles by Weissleder, R. Related Collections Related Article

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

Matthias Nahrendorf, MD, PhD^_*,,, Edmund Keliher, PhD^_*,, Peter Panizzi, PhD, Hanwen Zhang, PhD, Sheena Hembrador, BS, Jose-Luiz Figueiredo, MD^_*,, Elena Aikawa, MD, Kimberly Kelly, PhD, Peter Libby, MD^,, Ralph Weissleder, MD, PhD^_*,,,_*

^_* Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts
Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis at Harvard Medical School, Boston, Massachusetts
Cardiovascular Division, Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts

^_* Reprint requests and correspondence: Dr. Ralph Weissleder, Massachusetts General Hospital, Center for Systems Biology, CPZN-5206, 185 Cambridge Street, Boston, Massachusetts 02124 (Email: rweissleder{at}mgh.harvard.edu).

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.

Key Words: atherosclerosis • inflammation • molecular imaging • PET-CT • VCAM-1

Abbreviations and Acronyms   18F-4V = 18F-labeled tetrameric peptide-PET imaging reporter targeted to VCAM-1   18FDG = [18F]-fluorodeoxyglucose   ApoE = apolipoprotein E   DOTA = 1,4,7,10-tetraazadodecane-1,4,7,10-tetraacetic acid, chelator for 111-Indium labeling   MCP = monomeric cyclic peptide (DOTA-labeled)   MHEC = murine heart endothelial cells   MLP = monomeric linear peptide (DOTA-labeled)   MI = myocardial infarction   mRNA = messenger ribonucleic acid   %IDGT = percent injected dose/gram tissue   PET-CT = positron emission tomography-computed tomography   RT-PCR = reverse transcription polymerase chain reaction   TLP = tetrameric linear peptide (DOTA-labeled)   VCAM = vascular cell adhesion molecule

Related Article

Imaging Inflammation in Atherosclerosis: Another Step Forward

Prediman K. Shah
J. Am. Coll. Cardiol. Img. 2009 2: 1223-1225. [Full Text] [PDF]

This article has been cited by other articles:

				P. K. Shah Imaging Inflammation in Atherosclerosis: Another Step Forward J. Am. Coll. Cardiol. Img., October 1, 2009; 2(10): 1223 - 1225. [Full Text] [PDF]

				V. Dilsizian and J. Narula Putting the Face to a Name: Concurrent Assessment of Vascular Morphology and Biology J. Am. Coll. Cardiol. Img., October 1, 2009; 2(10): 1243 - 1244. [Full Text] [PDF]