PT  - JOURNAL ARTICLE
AU  - Mark G. MacAskill
AU  - Agne Stadulyte
AU  - Lewis Williams
AU  - Timaeus E. F. Morgan
AU  - Nikki L. Sloan
AU  - Carlos J. Alcaide-Corral
AU  - Tashfeen Walton
AU  - Catriona Wimberley
AU  - Chris-Anne McKenzie
AU  - Nick B. Spath
AU  - William Mungall
AU  - Ralph BouHaidar
AU  - Marc R. Dweck
AU  - Gillian A. Gray
AU  - David E. Newby
AU  - Christophe Lucatelli
AU  - Andrew Sutherland
AU  - Sally Pimlott
AU  - Adriana A. S. Tavares
TI  - Quantification of macrophage-driven inflammation during myocardial infarction with <sup>18</sup>F-LW223, a novel TSPO radiotracer with binding independent of the rs6971 human polymorphism
AID  - 10.2967/jnumed.120.243600
DP  - 2020 Aug 01
TA  - Journal of Nuclear Medicine
PG  - jnumed.120.243600
4099  - http://jnm.snmjournals.org/content/early/2020/08/27/jnumed.120.243600.short
4100  - http://jnm.snmjournals.org/content/early/2020/08/27/jnumed.120.243600.full
AB  - Rationale: Myocardial infarction (MI) is one of the leading causes of death worldwide and inflammation is central to the tissue response and patient outcomes. The 18kDa translocator protein (TSPO) has been utilized in positron emission tomography (PET) as an inflammatory biomarker. The aims of this study were to: 1) screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart, 2) assess whether the in vivo characteristics of our lead radiotracer, 18F-LW223, are suitable for clinical translation and 3) validate whether 18F-LW223 can detect macrophage driven inflammation in a rat myocardial infarction model. Methods: Fifty-one human brain and twenty-nine 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). Naive 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 invasive input function at 7 days following MI. For quantification of PET signal in the hypoperfused myocardium, K1 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 (62% 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 naive animals (36.9±8.8 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 following MI.