[11C]AZ10419369: A selective 5-HT1B receptor radioligand suitable for positron emission tomography (PET). Characterization in the primate brain

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Assessment of serotonin release in the living brain with positron emission tomography (PET) may have been hampered by the lack of suitable radioligands. We previously reported that fenfluramine caused a dose-dependent reduction in specific binding in monkeys using a classical displacement paradigm with bolus administration of [11 C]AZ10419369. The aim of this study was to confirm our previous findings using an equilibrium approach in monkey. A total of 24 PET measurements were conducted using a bolus infusion protocol of [11 C]AZ10419369 in three cynomolgus monkeys. Initial PET measurements were performed to assess suitable K bol values. The fenfluramine effect on [ 11 C]AZ10419369 binding was evaluated in a displacement and pretreatment paradigm. The effect of fenfluramine on [11 C]AZ10419369 binding potential (BP ND ) was dose-dependent in the displacement paradigm and confirmed in the pretreatment paradigm. After pretreatment administration of fenfluramine (5.0 mg/kg), the mean BP ND of the occipital cortex decreased by 39%, from 1.38 ± 0.04 to 0.84 ± 0.09. This study confirms that the new 5-HT 1B receptor radioligand [11 C]AZ10419369 is sensitive to fenfluramine-induced changes in endogenous serotonin levels in vivo. The more advanced methodology is suitable for exploring the sensitivity limit to serotonin release as measured using [11 C]AZ10419369 and PET.

Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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Confirmation of Fenfluramine Effect on 5-HT_1B Receptor Binding of [¹¹C]AZ10419369 using an Equilibrium Approach

Finnema

Varrone

Hwang

et al. 2011

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“…Only recently, two selective 5-HT 1B radioligands, [ 11 C]P943 (Nabulsi et al, 2007) and [ 11 C]AZ10419369 (Pierson et al, 2008), have been developed and evaluated in vivo as PET imaging agents.…”

Section: Introductionmentioning

confidence: 99%

Kinetic Modeling of the Serotonin 5-HT_1B Receptor Radioligand [¹¹C]P943 in Humans

Gallezot

Nabulsi

Neumeister

et al. 2009

[ 11 C]P943 is a new radioligand recently developed to image and quantify serotonin 5-Hydroxytryptamine (5-HT 1B ) receptors with positron emission tomography (PET). The purpose of this study was to evaluate [ 11 C]P943 for this application in humans, and to determine the most suitable quantification method. Positron emission tomography data and arterial input function measurements were acquired in a cohort of 32 human subjects. Using arterial input functions, compartmental modeling, the Logan graphical analysis, and the multilinear method MA1 were tested. Both the two tissue-compartment model and MA1 provided good fits of the PET data and reliable distribution volume estimates. Using the cerebellum as a reference region, BP ND binding potential estimates were computed.

“…[ 11 C]flumazenil (GABA A -receptor radioligand) was chosen because its quantification often requires an input function, since the suitability of the pons as a reference region has been questioned. 23 [ 11 C]AZ10419369 (5HT 1B -receptor radioligand) 24 was included to evaluate the approximation of venous sampling as a substitute to arterial sampling, since its negligible metabolism in human subjects permits to use the total radioactivity in plasma as an estimate of the input function without need of metabolite correction. 25 …”

Section: Rationale For Selection Of Radioligandsmentioning

confidence: 99%

Arterial Input Function Derived from Pairwise Correlations Between PET-image Voxels

Schain

Benjaminsson

Varnäs

et al. 2013

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A metabolite corrected arterial input function is a prerequisite for quantification of positron emission tomography (PET) data by compartmental analysis. This quantitative approach is also necessary for radioligands without suitable reference regions in brain. The measurement is laborious and requires cannulation of a peripheral artery, a procedure that can be associated with patient discomfort and potential adverse events. A non invasive procedure for obtaining the arterial input function is thus preferable. In this study, we present a novel method to obtain image-derived input functions (IDIFs). The method is based on calculation of the Pearson correlation coefficient between the time-activity curves of voxel pairs in the PET image to localize voxels displaying blood-like behavior. The method was evaluated using data obtained in human studies with the radioligands [ 11 C]flumazenil and [ 11 C]AZ10419369, and its performance was compared with three previously published methods. The distribution volumes (V T ) obtained using IDIFs were compared with those obtained using traditional arterial measurements. Overall, the agreement in V T was good (B3% difference) for input functions obtained using the pairwise correlation approach. This approach performed similarly or even better than the other methods, and could be considered in applied clinical studies. Applications to other radioligands are needed for further verification.