Molecular Imaging of Sirtuin1 Expression–Activity in Rat Brain Using Positron-Emission Tomography–Magnetic-Resonance Imaging with [18F]-2-Fluorobenzoylaminohexanoicanilide

Sirtuin 1 (SIRT1) is a class III histone deacetylase that plays significant roles in the regulation of lifespan, metabolism, memory, and circadian rhythms and in the mechanisms of many diseases. However, methods of monitoring the pharmacodynamics of SIRT1-targeted drugs are limited to blood sampling because of the invasive nature of biopsies. For the noninvasive monitoring of the spatial and temporal dynamics of SIRT1 expression–activity in vivo by PET–CT–MRI, we developed a novel substrate-type radiotracer, [18F]-2-fluorobenzoylaminohexanoicanilide (2-[18F]BzAHA). PET–CT–MRI studies in rats demonstrated increased accumulation of 2-[18F]BzAHA-derived radioactivity in the hypothalamus, hippocampus, nucleus accumbens, and locus coeruleus, consistent with autoradiographic and immunofluorescent (IMF) analyses of brain-tissue sections. Pretreatment with the SIRT1 specific inhibitor, EX-527 (5 mg/kg, ip), resulted in about a 20% reduction of 2-[18F]BzAHA-derived-radioactivity accumulation in these structures. I...