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

Abstract

Background Heat shock proteins (HSPs), ubiquitously found proteins called molecular chaperones in the brain, play important functional roles in the neuropathological processes of Alzheimer’s disease and Lewy body disease. Of many HSP subtypes, HSP90 has been shown to play a central role in the process. Many studies have shown that drugs that inhibit HSP90 activity have beneficial effects in the neurodegenerative diseases. Therefore, HSP90 PET imaging ligand, an in vivo biomarker of HSP90, 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 PET imaging ligand, [11C]NCGG801, selectively targeting HSP90α and HSP90β by radiolabeling BIIB021, an inhibitor with a high affinity for and selectivity to HSP90α and HSP90β. [11C]NCGG801 was synthesized with a high yield, molar activity and radiochemical purity. [11C]NCGG801 showed a high binding affinity for rat brain homogenate as well as human recombinant HSP90α and HSP90β proteins. This radioligand was well taken up into the rat brain (SUV 1.4) and showed clear specific binding in PET imaging of healthy rats and autoradiography of healthy rat and human brain sections. Conclusions Our data suggested that [11C]NCGG801 has a potential to be a new imaging biomarker of HSP90α/β in the brain. Further studies appear warranted to evaluate [11C]NCGG801 in humans.