TY - JOUR
T1 - 18F-4V for PET-CT Imaging of VCAM-1 Expression in Atherosclerosis
AU - Nahrendorf, Matthias
AU - Keliher, Edmund
AU - Panizzi, Peter
AU - Zhang, Hanwen
AU - Hembrador, Sheena
AU - Figueiredo, Jose Luiz
AU - Aikawa, Elena
AU - Kelly, Kimberly
AU - Libby, Peter
AU - Weissleder, Ralph
N1 - Funding Information:
This work was funded in part by the D.W. Reynolds Foundation (to Drs. Libby and Weissleder), UO1-HL080731 (to Dr. Weissleder), R01-HL078641 (to Dr. Weissleder), and R24-CA92782 (to Dr. Weissleder). Drs. Keliher, Panizzi, and Zhang contributed equally to this article.
PY - 2009/10
Y1 - 2009/10
N2 - 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.
AB - 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.
KW - PET-CT
KW - VCAM-1
KW - atherosclerosis
KW - inflammation
KW - molecular imaging
UR - http://www.scopus.com/inward/record.url?scp=70349777555&partnerID=8YFLogxK
U2 - 10.1016/j.jcmg.2009.04.016
DO - 10.1016/j.jcmg.2009.04.016
M3 - Article
C2 - 19833312
AN - SCOPUS:70349777555
SN - 1936-878X
VL - 2
SP - 1213
EP - 1222
JO - JACC: Cardiovascular Imaging
JF - JACC: Cardiovascular Imaging
IS - 10
ER -