• Max L Senders
  • Giuseppe Carlucci
  • Jan C van de Voort
  • Francois Fay
  • Claudia Calcagno
  • Jun Tang
  • Amr Alaarg
  • Yiming Zhao
  • Seigo Ishino
  • Anna Palmisano
  • Gilles Boeykens
  • Anu E Meerwaldt
  • Brenda L Sanchez-Gaytan
  • Samantha Baxter
  • Laura Zendman
  • Mark E Lobatto
  • Nicolas A Karakatsanis
  • Philip M Robson
  • Alexis Broisat
  • Jason S Lewis
  • Sotirios Tsimikas
  • Thomas Reiner
  • Zahi A Fayad
  • Willem J M Mulder
  • Carlos Pérez-Medina

OBJECTIVES: This study sought to develop an integrative positron emission tomography (PET) with magnetic resonance imaging (MRI) procedure for accurate atherosclerotic plaque phenotyping, facilitated by clinically approved and nanobody radiotracers.

BACKGROUND: Noninvasive characterization of atherosclerosis remains a challenge in clinical practice. The limitations of current diagnostic methods demonstrate that, in addition to atherosclerotic plaque morphology and composition, disease activity needs to be evaluated.

METHODS: We screened 3 nanobody radiotracers targeted to different biomarkers of atherosclerosis progression, namely vascular cell adhesion molecule (VCAM)-1, lectin-like oxidized low-density lipoprotein receptor (LOX)-1, and macrophage mannose receptor (MMR). The nanobodies, initially radiolabeled with copper-64 (64Cu), were extensively evaluated in Apoe-/- mice and atherosclerotic rabbits using a combination of in vivo PET/MRI readouts and ex vivo radioactivity counting, autoradiography, and histological analyses.

RESULTS: The 3 nanobody radiotracers accumulated in atherosclerotic plaques and displayed short circulation times due to fast renal clearance. The MMR nanobody was selected for labeling with gallium-68 (68Ga), a short-lived radioisotope with high clinical relevance, and used in an ensuing atherosclerosis progression PET/MRI study. Macrophage burden was longitudinally studied by 68Ga-MMR-PET, plaque burden by T2-weighted MRI, and neovascularization by dynamic contrast-enhanced (DCE) MRI. Additionally, inflammation and microcalcifications were evaluated by fluorine-18 (18F)-labeled fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF) PET, respectively. We observed an increase in all the aforementioned measures as disease progressed, and the imaging signatures correlated with histopathological features.

CONCLUSIONS: We have evaluated nanobody-based radiotracers in rabbits and developed an integrative PET/MRI protocol that allows noninvasive assessment of different processes relevant to atherosclerosis progression. This approach allows the multiparametric study of atherosclerosis and can aid in early stage anti-atherosclerosis drug trials.

Original languageEnglish
Pages (from-to)2015-2026
Number of pages12
JournalJACC: Cardiovascular Imaging
Issue number10
Early online date2018
Publication statusPublished - 1 Oct 2019

    Research areas

  • atherosclerosis, molecular imaging, nanobody, PET/MRI

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