title: Targeting of vascular cell adhesion molecule-1 by 18F-labelled nanobodies for PET/CT imaging of inflamed atherosclerotic plaques.
abstract: OBJECTIVE
  Positron emission tomography-computed tomography (PET-CT) is a highly sensitive clinical molecular imaging modality to study atherosclerotic plaque biology. Therefore, we sought to develop a new PET tracer, targeting vascular cell adhesion molecule (VCAM)-1 and validate it in a murine atherosclerotic model as a potential agent to detect atherosclerotic plaque inflammation.
  
  
  RESULTS
  The anti-VCAM-1 nanobody (Nb) (cAbVCAM-1-5) was radiolabelled with Fluorine-18 ((18)F), with a radiochemical purity of >98%. In vitro cell-binding studies showed specific binding of the tracer to VCAM-1 expressing cells. In vivo PET/CT imaging of ApoE(-/-) mice fed a Western diet or control mice was performed at 2h30 post-injection of [(18)F]-FB-cAbVCAM-1-5 or (18)F-control Nb. Additionally, plaque uptake in different aorta segments was evaluated ex vivo based on extent of atherosclerosis. Atherosclerotic lesions in the aortic arch of ApoE(-/-) mice, injected with [(18)F]-FB-anti-VCAM-1 Nb, were successfully identified using PET/CT imaging, while background signal was observed in the control groups. These results were confirmed by ex vivo analyses where uptake of [(18)F]-FB-cAbVCAM-1-5 in atherosclerotic lesions was significantly higher compared with control groups. Moreover, uptake increased with the increasing extent of atherosclerosis (Score 0: 0.68 ± 0.10, Score 1: 1.18 ± 0.36, Score 2: 1.49 ± 0.37, Score 3: 1.48 ± 0.38%ID/g, Spearman's r(2) = 0.675, P < 0.0001). High lesion-to-heart, lesion-to-blood, and lesion-to-control vessel ratios were obtained (12.4 ± 0.4, 3.3 ± 0.4, and 3.1 ± 0.6, respectively).
  
  
  CONCLUSIONS
  The [(18)F]-FB-anti-VCAM-1 Nb, cross-reactive for both mouse and human VCAM-1, allows non-invasive PET/CT imaging of VCAM-1 expression in atherosclerotic plaques in a murine model and may represent an attractive tool for imaging vulnerable atherosclerotic plaques in patients.
authors.affiliation: Centrum voor Hart-en Vaatziekten (CHVZ), UZ Brussel, Brussels, Belgium In Vivo Cellular and Molecular Imaging (ICMI), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, Brussels B-1090, Belgium gezim.bala@vub.ac.be.
authors.forename: Gezim
authors.initials: G
authors.lastname: Bala
authors.affiliation: In Vivo Cellular and Molecular Imaging (ICMI), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, Brussels B-1090, Belgium.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Blykers
authors.affiliation: In Vivo Cellular and Molecular Imaging (ICMI), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, Brussels B-1090, Belgium.
authors.forename: Catarina
authors.initials: C
authors.lastname: Xavier
authors.affiliation: iMinds-IBiTech-MEDISIP, Department of Electronics and Information Systems, Universiteit Gent, Ghent, Belgium.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Descamps
authors.affiliation: Radiopharmaceutiques Biocliniques, INSERM, 1039-Université de Grenoble, La Tronche, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Broisat
authors.affiliation: Radiopharmaceutiques Biocliniques, INSERM, 1039-Université de Grenoble, La Tronche, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ghezzi
authors.affiliation: Radiopharmaceutiques Biocliniques, INSERM, 1039-Université de Grenoble, La Tronche, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fagret
authors.affiliation: In Vivo Cellular and Molecular Imaging (ICMI), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, Brussels B-1090, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.affiliation: In Vivo Cellular and Molecular Imaging (ICMI), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, Brussels B-1090, Belgium Nuclear Medicine Department, UZ Brussel, Brussels, Belgium.
authors.forename: Vicky
authors.initials: V
authors.lastname: Caveliers
authors.affiliation: iMinds-IBiTech-MEDISIP, Department of Electronics and Information Systems, Universiteit Gent, Ghent, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Vanhove
authors.affiliation: In Vivo Cellular and Molecular Imaging (ICMI), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, Brussels B-1090, Belgium Nuclear Medicine Department, UZ Brussel, Brussels, Belgium.
authors.forename: Tony
authors.initials: T
authors.lastname: Lahoutte
authors.affiliation: Centrum voor Hart-en Vaatziekten (CHVZ), UZ Brussel, Brussels, Belgium In Vivo Cellular and Molecular Imaging (ICMI), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, Brussels B-1090, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Droogmans
authors.affiliation: Centrum voor Hart-en Vaatziekten (CHVZ), UZ Brussel, Brussels, Belgium In Vivo Cellular and Molecular Imaging (ICMI), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, Brussels B-1090, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Cosyns
authors.affiliation: In Vivo Cellular and Molecular Imaging (ICMI), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, Brussels B-1090, Belgium.
authors.forename: Nick
authors.initials: N
authors.lastname: Devoogdt
authors.affiliation: In Vivo Cellular and Molecular Imaging (ICMI), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, Brussels B-1090, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hernot
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D050197:Atherosclerosis / Q000000981:diagnostic imaging; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000528:radiation effects; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007249:Inflammation / Q000000981:diagnostic imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging*; D000072078:Positron Emission Tomography Computed Tomography; D011897:Random Allocation; D012680:Sensitivity and Specificity; D061905:Single-Domain Antibodies; D019010:Vascular Cell Adhesion Molecule-1 / Q000528:radiation effects*
chemical_list: D001057:Apolipoproteins E; D061905:Single-Domain Antibodies; D019010:Vascular Cell Adhesion Molecule-1; D019788:Fluorodeoxyglucose F18
keywords: PET/CT; VCAM-1; atherosclerosis; molecular imaging; nanobody