Kinetic modeling of [¹⁸F]VAT, a novel radioligand for positron emission tomography imaging vesicular acetylcholine transporter in non‐human primate brain

Abstract

Molecular imaging of vesicular acetylcholine transporter (VAChT) in the brain provides an important cholinergic biomarker for the pathophysiology and treatment of dementias including Alzheimer's disease. In this study, kinetics modeling methods were applied and compared for quantifying regional brain uptake of the VAChT-specific positron emission tomography radiotracer, ((-)-(1-(-8-(2-fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-fluorophenyl)-methanone) ([ F]VAT) in macaques. Total volume distribution (V ) estimates were compared for one-tissue compartment model (1TCM), two-tissue compartment model (2TCM), Logan graphic analysis (LoganAIF) and multiple linear analysis (MA1) with arterial blood input function using data from three macaques. Using the cerebellum-hemispheres as the reference region with data from seven macaques, three additional models were compared: reference tissue model (RTM), simplified RTM (SRTM), and Logan graphic analysis (LoganREF). Model selection criterion indicated that a) 2TCM and SRTM were the most appropriate kinetics models for [ F]VAT; and b) SRTM was strongly correlated with 2TCM (Pearson's coefficients r > 0.93, p < 0.05). Test-retest studies demonstrated that [ F]VAT has good reproducibility and reliability (TRV < 10%, ICC > 0.72). These studies demonstrate [ F]VAT is a promising VAChT positron emission tomography tracer for quantitative assessment of VAChT levels in the brain of living subjects.

In Vivo Characterization of Two 18F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains

“…The reconstructed PET images was coregistered with magnetization-prepared rapid gradient echo (MP-RAGE) MR images using Automated Image Registration (AIR), 46 and superimposed using Analyze 10.0 (AnalyzeDirect, Overland Park, KS). For quantitative analyses, a program VIDI that was coded by our PET imaging analysts and routinely used in our institute for PET data processing 47,48 was used. Regions of interest (ROIs) were manually drawn on MRI images for striatum and cerebellum, and transformed into PET images using the coregistration transformation matrix.…”

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

“…In contrast, large displacement of 18 F-VAT was observed upon administration of vesamicol in NHP (Table 3) [69,70]. Vesamicol is not selective for VAChT with wellknown binding to sigma receptors [71] and therefore represents a non-selective block.…”

“…For 18 F-FEOBV, the cerebellar grey matter has been validated as a suitable reference region and provided lower variability than arterial input measures, with high correlation, however, had a lower dynamic range [65]. In NHP, the cerebellum may also provide a reference region for 18 F-VAT quantification [70].…”

PET molecular imaging for pathophysiological visualization in Alzheimer’s disease

“…11 C-MK-6884 [82] and 18 F-ASEM [83] can be used to quantify the binding potential of the muscarinic and nicotinic acetylcholine receptors (mAChR and nAChR), respectively. And the imaging of vesicular acetylcholine transporter (VAChT) can be achieved by a series of compounds, such as 11 C-TZ659 [84], 18 F-VAT [85], and radiolabeled benzovesamicol VAChT analogs [86].…”