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Research ArticleCardiovascular
Open Access

Quantification of Macrophage-Driven Inflammation During Myocardial Infarction with 18F-LW223, a Novel TSPO Radiotracer with Binding Independent of the rs6971 Human Polymorphism

Mark G. MacAskill, Agne Stadulyte, Lewis Williams, Timaeus E.F. Morgan, Nikki L. Sloan, Carlos J. Alcaide-Corral, Tashfeen Walton, Catriona Wimberley, Chris-Anne McKenzie, Nick Spath, William Mungall, Ralph BouHaidar, Marc R. Dweck, Gillian A. Gray, David E. Newby, Christophe Lucatelli, Andrew Sutherland, Sally L. Pimlott and Adriana A.S. Tavares
Journal of Nuclear Medicine April 2021, 62 (4) 536-544; DOI: https://doi.org/10.2967/jnumed.120.243600
Mark G. MacAskill
1University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
2Edinburgh Imaging, University of Edinburgh, Edinburgh, United Kingdom
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Agne Stadulyte
1University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
2Edinburgh Imaging, University of Edinburgh, Edinburgh, United Kingdom
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Lewis Williams
3School of Chemistry, WestCHEM, University of Glasgow, Glasgow, United Kingdom
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Timaeus E.F. Morgan
3School of Chemistry, WestCHEM, University of Glasgow, Glasgow, United Kingdom
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Nikki L. Sloan
3School of Chemistry, WestCHEM, University of Glasgow, Glasgow, United Kingdom
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Carlos J. Alcaide-Corral
1University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
2Edinburgh Imaging, University of Edinburgh, Edinburgh, United Kingdom
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Tashfeen Walton
1University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
2Edinburgh Imaging, University of Edinburgh, Edinburgh, United Kingdom
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Catriona Wimberley
2Edinburgh Imaging, University of Edinburgh, Edinburgh, United Kingdom
4Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
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Chris-Anne McKenzie
5MRC Edinburgh Brain Tissue Bank, University of Edinburgh, Edinburgh, United Kingdom
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Nick Spath
1University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
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William Mungall
6Bioresearch and Veterinary Services, University of Edinburgh, Edinburgh, United Kingdom
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Ralph BouHaidar
7Forensic Pathology, University of Edinburgh, Edinburgh, United Kingdom
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Marc R. Dweck
1University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
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Gillian A. Gray
1University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
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David E. Newby
1University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
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Christophe Lucatelli
2Edinburgh Imaging, University of Edinburgh, Edinburgh, United Kingdom
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Andrew Sutherland
3School of Chemistry, WestCHEM, University of Glasgow, Glasgow, United Kingdom
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Sally L. Pimlott
8School of Medicine, University of Glasgow, Glasgow, United Kingdom; and
9NHS Greater Glasgow and Clyde, Glasgow, United Kingdom
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Adriana A.S. Tavares
1University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
2Edinburgh Imaging, University of Edinburgh, Edinburgh, United Kingdom
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  • FIGURE 1.
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    FIGURE 1.

    Radiosynthesis of 18F-LW223. Data are shown as mean ± SEM.

  • FIGURE 2.
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    FIGURE 2.

    LW223 binding to TSPO is not affected by human rs6971 genetic polymorphism. (A) Chemical structures of established (PK11195, PBR28) and novel (AB5186, LW223) TSPO ligands investigated. (B) Competition binding assays using these TSPO ligands in human brain homogenates genotyped and grouped as HAB, MAB, and LAB (PK11195: HAB = 6, MAB = 8, LAB = 4; PBR28: HAB = 4, MAB [2-site fitting] = 5, LAB = 4; AB5186: HAB = 6, MAB [2-site fitting] = 6, LAB = 5; LW223: HAB = 5, MAB = 5, LAB = 4). Only PK11195 and LW223 were not affected by polymorphism, as is also demonstrated in human heart homogenates (C) (PK11195: HAB = 4, MAB = 5, LAB = 4; PBR28: HAB = 4, MAB = 5, LAB = 4; AB5186: HAB = 4, MAB = 5 [2-site fitting], LAB = 4; LW223: HAB = 5, MAB = 5, LAB = 4).

  • FIGURE 3.
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    FIGURE 3.

    18F-LW223, assessed in naïve rats, has favorable metabolic profile and specifically targets TSPO in vivo. (A) Maximum-intensity projection of 18F-LW223 PET scan in naïve rat showing major uptake organs (left); metabolism of 18F-LW223 within rat blood showing high percentage of parent radiotracer within plasma up to 2 h after injection (middle, n = 3 per time point); and percentage of parent radiotracer within different tissues demonstrating low level of contaminating radiometabolites (right, n = 3). (B) SUV images of rat heart (left), lung (middle), and brain (right) at baseline (left side of each panel) and under TSPO blockade using prototypical TSPO ligand PK11195 (1 mg/kg, right side of each panel) demonstrating specificity of 18F-LW223 for this target. SUV PET images were filtered using gaussian 1 × 1 × 1 mm filter. (C) Total VT within heart (left), lung (middle), and brain (right) of naïve and TSPO-blocked rats. Results represent mean ± SEM (n = 6 for naïve; n = 3 for blocked). P values were obtained using unpaired t test. A = adrenal glands; B = brain; G = gut; H = heart; K = kidney; L = lung. *P < 0.05. **P ≤ 0.01. ***P ≤ 0.001.

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    FIGURE 4.

    18F-LW223 PET with BPTC quantification detects macrophage-driven inflammation within heart 7 d after MI without need for additional perfusion scan. (A) Long-axis representative SUV image of heart in naïve and MI rats showing increased global uptake and lack of signal within LV anterior wall due to MI-mediated reduction in perfusion (left) (images were filtered using gaussian 1 × 1 × 1 mm filter)); non–perfusion-corrected VT within global heart and LV anterior wall, which was site of infarct (middle); and K1 acting as surrogate marker of perfusion, being reduced within LV anterior wall (right). (B) Representative K1 (left) and BPTC images (middle) of LV of MI rat demonstrating true TSPO signal across heart; BPTC values across global heart and LV anterior wall demonstrating that most TSPO is expressed within infarct (right). n = 6 for natïve and n = 9 for MI. (C) Representative histology examples of hearts from naïve (top) and MI (bottom) rat. Hematoxylin and eosin (H&E) overview (scale bar = 1,000 μm) contains box that indicates position of CD68 examples (macrophage marker) and TSPO examples (scale bar = 50 μm), demonstrating specificity of TSPO for macrophages, which are mostly present within infarct. (D) Quantification of TSPO immunofluorescent stain indicating that most signal is present within LV anterior wall (left), as is also true for CD68 quantification (middle); comparison of TSPO and CD68 indicates significant correlation within heart (right). n = 3 for naïve and n = 5 for MI. All results represent mean ± SEM. P values were obtained using 2-way ANOVA with post hoc Sidak for naïve vs. MI, apart from correlation analysis, which used Pearson correlation. A = anterior; P = posterior. **P ≤ 0.01. ***P ≤ 0.001. ****P ≤ 0.0001.

  • FIGURE 5.
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    FIGURE 5.

    Heart–brain axis in health and after MI. (A) Representative 18F-LW223 brain (top, coronal section) and heart (bottom, short axis) PET/CT images of naïve and MI rats (left); CD68 (red) and TSPO (green) immunofluorescence within same animals (middle, scale bar = 1,000 μm); and regional brain immunofluorescence within lateral ventricles of naïve (top) and MI (second from top) rats and within thalamus of naïve (second from bottom) and MI (bottom, scale bar = 20 μm) rats. White arrowheads denote cells that are both CD68- and TSPO-positive; pink arrowheads denote cells positive only for CD68. Cells positive only for TSPO were abundant and are not specifically denoted. (B) Comparison of 18F-LW223 VT in heart and brain of naïve and MI rats showing strong correlation, (n = 15), as is also true for TSPO (n = 8) and CD68 (n = 8). P values were obtained using Pearson correlation. **P ≤ 0.01. **P ≤ 0.0001.

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    TABLE 1

    Estimated 18F-LW223 Radiation Dose for Humans Is Within Acceptable Limits for Future Clinical Use

    Estimated absorbed dose (×10−2 mGy/MBq)
    Target organMale (n = 8)Female (n = 5)
    Adrenals2.223.67
    Brain0.590.56
    Breasts0.720.86
    Gallbladder wall2.012.46
    Lower large intestine wall7.829.26
    Small intestine1.111.30
    Stomach wall0.941.15
    Upper large intestine wall1.001.24
    Heart wall2.031.89
    Kidneys1.571.54
    Liver1.301.95
    Lung3.103.31
    Muscle0.800.98
    Ovaries—1.66
    Pancreas1.031.26
    Red marrow0.820.98
    Osteogenic cells1.201.52
    Skin0.610.74
    Spleen0.911.11
    Testes0.77—
    Thymus0.901.07
    Thyroid0.790.89
    Urinary bladder wall1.161.48
    Uterus—1.29
    Total body0.891.07
    Effective dose (mSv/MBq)0.020.02

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Journal of Nuclear Medicine: 62 (4)
Journal of Nuclear Medicine
Vol. 62, Issue 4
April 1, 2021
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Quantification of Macrophage-Driven Inflammation During Myocardial Infarction with 18F-LW223, a Novel TSPO Radiotracer with Binding Independent of the rs6971 Human Polymorphism
Mark G. MacAskill, Agne Stadulyte, Lewis Williams, Timaeus E.F. Morgan, Nikki L. Sloan, Carlos J. Alcaide-Corral, Tashfeen Walton, Catriona Wimberley, Chris-Anne McKenzie, Nick Spath, William Mungall, Ralph BouHaidar, Marc R. Dweck, Gillian A. Gray, David E. Newby, Christophe Lucatelli, Andrew Sutherland, Sally L. Pimlott, Adriana A.S. Tavares
Journal of Nuclear Medicine Apr 2021, 62 (4) 536-544; DOI: 10.2967/jnumed.120.243600

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Quantification of Macrophage-Driven Inflammation During Myocardial Infarction with 18F-LW223, a Novel TSPO Radiotracer with Binding Independent of the rs6971 Human Polymorphism
Mark G. MacAskill, Agne Stadulyte, Lewis Williams, Timaeus E.F. Morgan, Nikki L. Sloan, Carlos J. Alcaide-Corral, Tashfeen Walton, Catriona Wimberley, Chris-Anne McKenzie, Nick Spath, William Mungall, Ralph BouHaidar, Marc R. Dweck, Gillian A. Gray, David E. Newby, Christophe Lucatelli, Andrew Sutherland, Sally L. Pimlott, Adriana A.S. Tavares
Journal of Nuclear Medicine Apr 2021, 62 (4) 536-544; DOI: 10.2967/jnumed.120.243600
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