02 Apr 21. Featured Paper

Quantification of macrophage-driven inflammation during myocardial infarction with 18F-LW223, a novel TSPO radiotracer with binding independent of the rs6971 human polymorphism.

Link to paper on Journal of Nuclear Medicine

Authors

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

Abstract

Myocardial infarction (MI) is one of the leading causes of death worldwide, & inflammation is central to tissue response & 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 & heart; assess whether the in vivo characteristics of our lead radiotracer, ¹⁸F-LW223, are suitable for clinical translation; & validate whether ¹⁸F-LW223 can detect macrophage-driven inflammation in a rat MI model. 

Methods: Fifty-one human brain & 29 human heart tissue samples were screened for the rs6971 polymorphism.

Competition binding assays were conducted with ³H-PK11195 & the following ligands: PK11195, PBR28, & our novel compounds (AB5186 & LW223).

Naïve rats & mice were used for in vivo PET kinetic studies, radiometabolite studies, & dosimetry experiments.

Rats underwent permanent coronary artery ligation & 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 (BP_TC). 

Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain & 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%, & a suitable dosimetry profile (effective dose of 20.5–24.5 μSv/MBq).

¹⁸F-LW223 BP_TC 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 & CD68 (macrophage marker) resulted in the same pattern seen with in vivo BP_TC analysis. 

Conclusion: ¹⁸F-LW223 is not susceptible to the rs6971 genetic polymorphism in in vitro assays, has favorable in vivo characteristics, & is able to accurately map macrophage-driven inflammation after MI.

Keywords

• Inflammation
• Macrophage
• Myocardial infarction
• PET
• TSPO