Mark G MacAskill et al., The Journal of Nuclear Medicine, 2020
Cardiovascular disease is the leading cause of morbidity and mortality worldwide. A large proportion of these fatalities is due to myocardial infarction (MI). Acute inflammation is a key driver of pathology determining disease perturbation after tissue infarction.
The 18-kDa translocator protein (TSPO) is expressed within the outer membrane of the mitochondria, where it is a key factor in controlling the transport of cholesterol necessary for steroid hormone synthesis. TSPO is highly expressed within inflammatory cells such as macrophages in the periphery and microglia in the brain and has consequently been used as a marker of inflammation in pathologies throughout the body.
Although TSPO is one of the most widely explored targets in the field of PET, clinical adoption of this tissue biomarker has been globally hindered by radiotracers with suboptimal properties. For example, the prototypical TSPO ligand 11C-PK11195 has relatively high nonspecific binding and a short half-life. Efforts to surpass the limitations of 11C-PK11195 have been hampered primarily by the differential binding of second-generation TSPO radiotracers now known to be caused by the rs6971 genetic polymorphism. Moreover, 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. Previously, quantification of regional tissue inflammation after MI has relied on the use of TSPO PET static imaging and SPECT perfusion static scans for correction of the TSPO PET data.
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 the authors' lead radiotracer is suitable for clinical translation; and validate whether this novel TSPO radiotracer can detect macrophage-driven inflammation in a rat MI model.
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