A novel PET probe to selectively image heat shock protein 90α/β isoforms in the brain

Springer Science and Business Media LLC
Takayuki Sakai1, Aya Ogata1, Hiroshi Ikenuma1, Takashi Yamada1, Saori Hattori1, Jiro Abe1, Shinichi Imamura1, Masanori Ichise1, Mari Tada2, Akiyoshi Kakita2, Hiroko Koyama3, Masaaki Suzuki3, Takashi Kato1, Kengo Ito1, Yasuyuki Kimura1
1Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, Research Institute, National Center for Geriatrics and Gerontology (NCGG), 7-430 Morioka-cho, Obu, Aichi, 474-8511, Japan
2Department of Pathology; Brain Research Institute; Niigata University; Niigata Japan
3Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu, Japan

Tóm tắt

Abstract Background Heat shock proteins (HSPs) are present throughout the brain. They function as molecular chaperones, meaning they help with the folding and unfolding of large protein complexes. These chaperones are vital in the development of neuropathological conditions such as Alzheimer’s disease and Lewy body disease, with HSP90, a specific subtype of HSP, playing a key role. Many studies have shown that drugs that inhibit HSP90 activity have beneficial effects in the neurodegenerative diseases. Therefore, HSP90 PET imaging ligand can be used effectively to study HSP90 in neurodegenerative diseases. Among four HSP90 isoforms, two cytosolic isoforms (HSP90α and HSP90β) thought to be involved in the structural homeostasis of the proteins related to the neurodegenerative diseases. Currently, no useful PET imaging ligands selectively targeting the two cytosolic isoforms of HSP90 have been available yet. Results In this study, we developed a novel positron emission tomography (PET) imaging ligand, [11C]BIIB021, by 11C-radiolabeling (a positron emitter with a half-life of 20.4 min) 6-Chloro-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9H-purin-2-amine (BIIB021), an inhibitor with a high affinity for and selectivity to HSP90α and HSP90β. [11C]BIIB021 was synthesized with a high yield, molar activity and radiochemical purity. [11C]BIIB021 showed a high binding affinity for rat brain homogenate as well as human recombinant HSP90α and HSP90β proteins. Radioactivity was well detected in the rat brain (SUV 1.4). It showed clear specific binding in PET imaging of healthy rats and autoradiography of healthy rat and human brain sections. Radiometabolite was detected in the brain, however, total distribution volume was well quantified using dual-input graphical model. Inhibition of p-glycoprotein increased brain radioactivity concentrations. However, total distribution volume values with and without p-glycoprotein inhibition were nearly the same. Conclusions We have developed a new PET imaging agent, [11C]BIIB021, specifically targeting HSP90α/β. We have been successful in synthesizing [11C]BIIB021 and in vitro and in vivo imaging HSP90α/β. However, the quantification of HSP90α/β is complicated by the presence of radiometabolites in the brain and the potential to be a substrate for p-glycoprotein. Further efforts are needed to develop radioligand suitable for imaging of HSP90α/β.

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