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.
Highlights
Cardiovascular disease is the leading cause of morbidity and mortality worldwide [1]
Efforts to surpass the limitations of 11C-PK11195 have been hampered primarily by the differential binding of second-generation translocator protein (TSPO) radiotracers known to be caused by the rs6971 genetic polymorphism [13]
This study aimed to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using the gold standard in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer is suitable for clinical translation; and validate whether our novel TSPO radiotracer can detect macrophagedriven inflammation in a rat myocardial infarction (MI) model
Summary
Cardiovascular disease is the leading cause of morbidity and mortality worldwide [1]. Acute inflammation is a key driver of pathology determining disease perturbation after tissue infarction [2]. Efforts to surpass the limitations of 11C-PK11195 have been hampered primarily by the differential binding of second-generation TSPO radiotracers known to be caused by the rs6971 genetic polymorphism [13]. The use of TSPO PET radiotracers in the context of cardiovascular disease, in particular after MI, has faced limited adoption due to lack of validated paradigms for quantification of regional tissue inflammation in hypoperfused areas using a single technique or scan. There is a need to develop improved TSPO PET ligands and methodology to boost adoption of this technology for noninvasive imaging of inflammation in cardiology. This study aimed to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using the gold standard in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer is suitable for clinical translation; and validate whether our novel TSPO radiotracer can detect macrophagedriven inflammation in a rat MI model
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