Novel radioligands for imaging sigma-1 receptor in brain using positron emission tomography(PET)

The sigma-1 receptor(σ1R)is a unique intracellular protein.σ1R plays a major role in various pathological conditions in the central nervous system(CNS),implicated in several neuropsychiatric disorders.Imaging ofσ1R in the brain using positron emission tomography(PET)could serve as a noninvasively tool for enhancing the understanding of the disease’s pathophysiology.Moreover,σ1R PET tracers can be used for target validation and quantification in diagnosis.Herein,we describe the radiosynthesis,in vivo PET/CT imaging of novelσ1R11C-labeled radioligands based on 6-hydroxypyridazinone,[11C]HCC0923 and[11C]HCC0929.Two radioligands have high affinities toσ1R,with good selectivity.In mice PET/CT imaging,both radioligands showed appropriate kinetics and distributions.Additionally,the specific interactions of two radioligands were reduced by compounds 13 and 15(self-blocking).Ofthe two,[11C]HCC0929 was further investigated in positive ligands blocking studies,using classicσ1R agonist SA 4503 andσ1R antagonist PD 144418.Bothσ1R ligands could extensively decreased the uptake of[11C]HCC0929 in mice brain.Besides,the biodistribution of major brain regions and organs of mice were determined in vivo.These studies demonstrated that two radioligands,especially[11C]HCC0929,possessed ideal imaging properties and might be valuable tools for non-invasive quantification ofσ1R in brain.

Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease

Although the epigenetic regulatory protein histone deacetylase 6(HDAC6)has been recently implicated in the etiology of Alzheimer’s disease(AD),little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD.Here,we performed positron emission tomography(PET)imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD.We first developed[^(18)F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6.PET studies of[^(18)F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals,with more pronounced changes identified in the cortex and hippocampus.The translatability of this radiotracer for AD in a potential human use was supported by additional studies,including similar uptake profiles in non-human primates,an increase of HDAC6 in ADrelated human postmortem hippocampal tissues by Western blotting protein analysis,and our ex vivo histopathological analysis of HDAC6 in postmortem brain tissues of our animals.Collectively,our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly susceptible to AD through an association with amyloid pathology.