TY - JOUR
T1 - Molecular Imaging of Sirtuin1 Expression-Activity in Rat Brain Using Positron-Emission Tomography-Magnetic-Resonance Imaging with [18F]-2-Fluorobenzoylaminohexanoicanilide
AU - Bonomi, Robin
AU - Popov, Vadim
AU - Laws, Maxwell T.
AU - Gelovani, David
AU - Majhi, Anjoy
AU - Shavrin, Aleksandr
AU - Lu, Xin
AU - Muzik, Otto
AU - Turkman, Nashaat
AU - Liu, Renshyan
AU - Mangner, Thomas
AU - Gelovani, Juri G.
N1 - Publisher Copyright:
© Copyright 2018 American Chemical Society.
PY - 2018/8/23
Y1 - 2018/8/23
N2 - 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. In vivo imaging of SIRT1 expression-activity should facilitate studies that improve the understanding of SIRT1-mediated regulation in the brain and aid in the development and clinical translation of SIRT1-targeted therapies.
AB - 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. In vivo imaging of SIRT1 expression-activity should facilitate studies that improve the understanding of SIRT1-mediated regulation in the brain and aid in the development and clinical translation of SIRT1-targeted therapies.
UR - http://www.scopus.com/inward/record.url?scp=85050974570&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b00253
DO - 10.1021/acs.jmedchem.8b00253
M3 - Article
C2 - 30052441
AN - SCOPUS:85050974570
SN - 0022-2623
VL - 61
SP - 7116
EP - 7130
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -