Quantitative Analysis of [¹¹C]AZ10419369 Binding to 5-HT_1B Receptors in Human Brain

Abstract

A novel radioligand for positron emission tomography (PET) imaging of serotonin 5-HT1B receptors, [11C]AZ10419369, has been recently described. In this study, the potential for quantitative analysis of [11C]AZ10419369 binding to central 5-HT1B receptors was evaluated in human subjects. PET measurements were performed after injection of [11C]AZ10419369 in 10 subjects. Data were analyzed with kinetic modeling and linear graphical analysis using the arterial plasma as input function, and with reference tissue models using cerebellar cortex as the reference region. Binding of [11C]AZ10419369 was highest in pallidum, ventral striatum, and occipital cortex and lowest in cerebellum. The percentage of unchanged radioligand in plasma was 97% to 99%, indicating that no significant amounts of radioactive metabolites were formed during the time of analysis. Time–activity curves of [11C]AZ10419369 could be described with both one-tissue compartment (1-TC) and two-tissue compartment (2-TC) models in the majority of subjects. The 2-TC model failed to deliver reasonable estimates of the kinetic parameters. However, stable estimates of binding potential ( BPND) were obtained by constraining K1/ k2 to the distribution volume obtained with the 1-TC model in the cerebellar cortex. BPND values estimated with reference tissue models were correlated with the corresponding values obtained with kinetic modeling. The findings support the use of reference tissue models in applied clinical studies with [11C]AZ10419369.

Confirmation of Fenfluramine Effect on 5-HT1B Receptor Binding of [11C]AZ10419369 using an Equilibrium Approach

“…Previously, we reported that [ 11 C]AZ10419369 is suitable for in vivo quantification of 5-HT 1B receptors in the brain of monkey and man (Pierson et al, 2008;Varnäs et al, 2011a). Of the 14 serotonin receptors, the 5-HT 1A and the 5-HT 1B receptor are the two receptors located presynaptically (Barnes and Sharp, 1999).…”

Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369

“…In a collaboration between Karolinska Institutet and AstraZeneca, a 5-HT 1B receptor selective compound, AZ10419369, has recently been labeled with carbon-11 ) and characterized as a suitable radioligand for quantification of 5-HT 1B receptor binding in the human brain in vivo (Varnäs et al 2010). This radioligand now represents a promising tool for quantification of receptor occupancy induced by compounds targeting the 5-HT 1B receptor.…”

No correlation between serotonin and its metabolite 5-HIAA in the cerebrospinal fluid and [11C]AZ10419369 binding measured with PET in healthy volunteers

“…The examination with PET and [ 11 C]AZ10419369 was performed as previously described (Varnas et al, 2011). The mean (6s.d.)…”

“…The cerebellum was chosen as reference region, due to its negligible 5-HT 1B receptor density (Varnas et al, 2001), and defined manually. The simplified reference tissue model has been validated for calculation of [ 11 C]AZ10419369 BP ND in humans (Varnas et al, 2011) and was applied within Matlab R2007b for Windows.…”