Abstract
BackgroundPrevious studies found that [18F]LSN3316612 was a promising positron emission tomography (PET) radioligand for imaging O-GlcNAcase in nonhuman primates and human volunteers. This study sought to further evaluate the suitability of [18F]LSN3316612 for human clinical research.MethodsKinetic evaluation of [18F]LSN3316612 was conducted in a combined set of baseline brain scans from 17 healthy human volunteers and test-retest imaging was conducted in 10 of these volunteers; another 6 volunteers had whole-body scans to measure radiation exposure to body organs. Total distribution volume (VT) estimates were compared for the one- and two-tissue compartment models with the arterial input function. Test-retest variability and reliability were evaluated via mean difference and intraclass correlation coefficient (ICC). The time stability of VT was assessed down to a 30-min scan time. An alternative quantification method for [18F]LSN3316612 binding without blood was also investigated to assess the possibility of eliminating arterial sampling.ResultsBrain uptake was generally high and could be quantified as VT with excellent identifiability using the two-tissue compartment model. [18F]LSN3316612 exhibited good absolute test-retest variability (12.5%), but the arithmetic test-retest variability was far from 0 (11.3%), reflecting a near-uniform increase of VT on the retest scan in nine of 10 volunteers. VT values were stable after 110 min in all brain regions, suggesting that no radiometabolites accumulated in the brain. Measurements obtained using only brain activity (i.e., area under the curve (AUC) from 150–180 min) correlated strongly with regional VT values during test-retest conditions (R2 = 0.84), exhibiting similar reliability to VT (ICC = 0.68 vs. 0.64). Estimated radiation exposure for [18F]LSN3316612 PET was 20.5 ± 2.1 μSv/MBq, comparable to other 18F-labeled radioligands for brain imaging.Conclusions[18F]LSN3316612 is an excellent PET radioligand for imaging O-GlcNAcase in the human brain. Alternative quantification without blood is possible, at least for within-subject repeat studies. However, the unexplained increase of VT under retest conditions requires further investigation.
Highlights
O-GlcNAcylation is a common post-transcriptional glycosylation that occurs extensively at the intracellular level of the brain [1]. This reversible cycling is modulated by two enzymes; O-linked β-N-acetylglucosamine (OGlcNAc) transferase attaches O-GlcNAc to a protein, whereas O-GlcNAcase (OGA) removes it [2]
Study population and injection parameters As noted above, 17 baseline scans were analyzed for kinetic evaluation of [18F]LSN3316612 in the brain; 7 volunteers had a single scan and 10 volunteers had test-retest scans
An arbitrary decision was made to use the first scan for those volunteers who had test-retest scans
Summary
O-GlcNAcylation is a common post-transcriptional glycosylation that occurs extensively at the intracellular level of the brain [1]. This reversible cycling is modulated by two enzymes; O-linked β-N-acetylglucosamine (OGlcNAc) transferase attaches O-GlcNAc to a protein, whereas O-GlcNAcase (OGA) removes it [2]. Initial ex vivo research supported the reciprocal relationship OGlcNAcylation and phosphorylation [6], and analysis of human brain tissue revealed lower levels of tau-specific and overall O-GlcNAc in individuals with AD [7]. A series of animal studies found that increased O-GlcNAcylation cycling by an OGA inhibitor reduced tau protein aggregation and restored cognitive function [8,9,10]. This study sought to further evaluate the suitability of [18F]LSN3316612 for human clinical research
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