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Macrophage PET imaging in mouse models of cardiovascular disease and cancer with an apolipoprotein-inspired radiotracer


Yohana C Toner, A JP Teunissen and Carlos Perez-Medina et al.

NPJ Imaging, 2024


Macrophages are key inflammatory mediators in many pathological conditions, including cardiovascular disease (CVD) and cancer, the leading causes of morbidity and mortality worldwide. This makes macrophage burden a valuable diagnostic marker and several strategies to monitor these cells have been reported. However, such strategies are often high-priced, non-specific, invasive, and/or not quantitative. Here, we developed a positron emission tomography (PET) radiotracer based on apolipoprotein A1 (ApoA1), the main protein component of high-density lipoprotein (HDL), which has an inherent affinity for macrophages. We radiolabeled an ApoA1-mimetic peptide (mA1) with zirconium-89 (89Zr) to generate a lipoprotein-avid PET probe (89Zr-mA1). We first characterized 89Zr-mA1’s affinity for lipoproteins in vitro by size exclusion chromatography. To study 89Zr-mA1’s in vivo behavior and interaction with endogenous lipoproteins, we performed extensive studies in wildtype C57BL/6 and Apoe-/- hypercholesterolemic mice. Subsequently, we used in vivo PET imaging to study macrophages in melanoma and myocardial infarction using mouse models. The tracer’s cell specificity was assessed by histology and mass cytometry (CyTOF). Our data show that 89Zr-mA1 associates with lipoproteins in vitro. This is in line with our in vivo experiments, in which we observed longer 89Zr-mA1 circulation times in hypercholesterolemic mice compared to C57BL/6 controls. 89Zr-mA1 displayed a tissue distribution profile similar to ApoA1 and HDL, with high kidney and liver uptake as well as substantial signal in the bone marrow and spleen. The tracer also accumulated in tumors of melanoma-bearing mice and in the ischemic myocardium of infarcted animals. In these sites, CyTOF analyses revealed that natZr-mA1 was predominantly taken up by macrophages. Our results demonstrate that 89Zr-mA1 associates with lipoproteins and hence accumulates in macrophages in vivo. 89Zr-mA1’s high uptake in these cells makes it a promising radiotracer for non-invasively and quantitatively studying conditions characterized by marked changes in macrophage burden.

Results from nanoScan® PET/CT

  • Authors  have developed an apolipoprotein A1 mimetic-based radiotracer for monitoring macrophage burden
  • They also demonstrated 89Zr-mA1’s applicability toward imaging macrophage accumulation in the infarcted myocardium
  • Increased tracer uptake was observed in the infarcted area both in vivo and ex vivo
  • Authors recommend overnight fasting or avoiding fat-rich meals prior to the imaging session
  • 89Zr-mA1’s infarct-to-remote myocardium uptake ratios were similar or higher compared to other reported tracers, such as 18F-Macroflor, 64Cu-Macrin, and 68Ga-Pentixafor

Dynamic PET imaging was performed on a cohort of C57BL/6 animals (n = 4 per group) for 60 min after 89Zr-mA1 administration. These mice were anesthetized with isoflurane (2% in medical air for induction, 1% for maintenance) and placed on the bed of a nanoScan PET/CT scanner (Mediso, Budapest, Hungary). Following a scout scan, a full-body CT was performed, and a 60-min dynamic PET scan with a field of view aligned with the full positioning of the mouse was initiated right after injection of 89Zr-mA1 (3.4 MBq) via the lateral tail vein. Upon completion of the scan, a total of 5 dynamic frames were individually reconstructed for the following timepoints: 1, 5, 15, 30, and 60 min.

Fig. 2 A Representative 3D-rendered PET/CT images of C57BL/6 mice were scanned dynamically for 1 h following 89Zr-mA1 injection. B 89Zr-mA1 pharmacokinetics in specific tissues (n = 4). C Representative 3D-rendered PET/CT image of a C57BL/6 mouse 24 h after i.v. tracer injection. D Ex vivo biodistribution as assessed by gamma counting of tissues of interest 24 h p.i. (n = 5). E Ex vivo biodistribution as assessed by gamma counting of tissues of interest 24 h p.i. (n = 5) in mice treated with clodronate liposomes. Matched controls that did not receive clodronate injections are represented in gray.

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