MacAskill, M. G. et al. (2021) Quantification of macrophage-driven inflammation during myocardial infarction with 18F-LW223, a novel TSPO radiotracer with binding independent of the rs6971 human polymorphism. Journal of Nuclear Medicine, 62(4), pp. 536-544. (doi: 10.2967/jnumed.120.243600) (PMID:32859708) (PMCID:PMC8049364)
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Abstract
Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, 18F-LW223, are suitable for clinical translation; and validate whether 18F-LW223 can detect macrophage-driven inflammation in a rat MI model. Methods: Fifty-one human brain and 29 human heart tissue samples were screened for the rs6971 polymorphism. Competition binding assays were conducted with 3H-PK11195 and the following ligands: PK11195, PBR28, and our novel compounds (AB5186 and LW223). Naïve rats and mice were used for in vivo PET kinetic studies, radiometabolite studies, and dosimetry experiments. Rats underwent permanent coronary artery ligation and were scanned using PET/CT with an invasive input function at 7 d after MI. For quantification of PET signal in the hypoperfused myocardium, K1 (rate constant for transfer from arterial plasma to tissues) was used as a surrogate marker of perfusion to correct the binding potential for impaired radiotracer transfer from plasma to tissue (BPTC). Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain and heart samples. In rodents, 18F-LW223 displayed a specific uptake consistent with TSPO expression, a slow metabolism in blood (69% of parent at 120 min), a high plasma free fraction of 38.5%, and a suitable dosimetry profile (effective dose of 20.5–24.5 μSv/MBq). 18F-LW223 BPTC was significantly higher in the MI cohort within the infarct territory of the anterior wall relative to the anterior wall of naïve animals (32.7 ± 5.0 vs. 10.0 ± 2.4 cm3/mL/min, P ≤ 0.001). Ex vivo immunofluorescent staining for TSPO and CD68 (macrophage marker) resulted in the same pattern seen with in vivo BPTC analysis. Conclusion: 18F-LW223 is not susceptible to the rs6971 genetic polymorphism in in vitro assays, has favorable in vivo characteristics, and is able to accurately map macrophage-driven inflammation after MI.
| Item Type: | Articles |
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| Additional Information: | This work was funded by the British Heart Foundation (PG/16/12/32022 and PG/17/83/ 33370) and the Engineering and Physical Sciences Research Council (EPSRC Impact Acceleration Awards, EP/K5039031 and EP/ R511705/1). The British Heart Foundation is greatly acknowledged for providing funding toward establishment of the preclinical PET/ CT laboratory at the University of Edinburgh (RE/13/3/30183) and radiometabolite laboratories (RG/16/10/32375). Adriana Tavares and Tashfeen Walton are funded by the British Heart Foundation (RG/16/10/32375 and FS/19/34/34354). Mark MacAskill is funded by the British Heart Foundation (PG/16/12/32022, PG/17/83/33370, and RG/16/10/32375), and Agne Stadulyte is funded by the British Heart foundation (RE/13/3/30183). David Newby is funded by the British Heart Foundation (CH/09/002, RG/16/10/32375, and RE/18/ 5/34216) and is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Sloan, Dr Nikki and Pimlott, Dr Sally and Morgan, Mr Timaeus and Sutherland, Professor Andrew and Williams, Mr Lewis |
| Authors: | MacAskill, M. G., Stadulyte, A., Williams, L., Morgan, T. E. F., Sloan, N. L., Alcaide-Corral, C. J., Walton, T., Wimberley, C., McKenzie, C.-A., Spath, N., Mungall, W., BouHaidar, R., Dweck, M. R., Gray, G. A., Newby, D. E., Lucatelli, C., Sutherland, A., Pimlott, S. L., and Tavares, A. A.S. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing College of Science and Engineering > School of Chemistry |
| Journal Name: | Journal of Nuclear Medicine |
| Publisher: | Society of Nuclear Medicine |
| ISSN: | 0161-5505 |
| ISSN (Online): | 2159-662X |
| Published Online: | 29 March 2021 |
| Copyright Holders: | Copyright © 2021 by the Society of Nuclear Medicine and Molecular Imaging |
| First Published: | First published in Journal of Nuclear Medicine 62(4): 536-544 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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