18F-4V for PET-CT imaging of VCAM-1 expression in atherosclerosis.
OBJECTIVE
The aim of this study was to iteratively develop and validate an (18)F-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 (18)F-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 (18)F-4V showed 0.31 +/- 0.02 SUV in murine atheroma (ex vivo %IDGT 5.9 +/- 1.5). (18)F-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, (18)F-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
(18)F-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.
Nahrendorf
Matthias
M
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02124, USA.
Keliher
Edmund
E
Panizzi
Peter
P
Zhang
Hanwen
H
Hembrador
Sheena
S
Figueiredo
Jose-Luiz
JL
Aikawa
Elena
E
Kelly
Kimberly
K
Libby
Peter
P
Weissleder
Ralph
R
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000276:immunology; D000069059:Atorvastatin; D001667:Binding, Competitive; D002478:Cells, Cultured; D003287:Contrast Media; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging* / Q000276:immunology; D005240:Feasibility Studies; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006084:Graft Rejection / Q000000981:diagnostic imaging / Q000276:immunology; D006207:Half-Life; D016027:Heart Transplantation; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000000981:diagnostic imaging / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism*; D007479:Iopamidol; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000276:immunology; D010455:Peptides / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011237:Predictive Value of Tests; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
D001057:Apolipoproteins E; D003287:Contrast Media; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D008024:Ligands; D010455:Peptides; D011758:Pyrroles; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; D019010:Vascular Cell Adhesion Molecule-1; D019788:Fluorodeoxyglucose F18; D000069059:Atorvastatin; D007479:Iopamidol