Functional Characterization of 5-HT_1BReceptor Drugs in Nonhuman Primates Using Simultaneous PET-MR

Abstract

In the present study, we used a simultaneous PET-MR experimental design to investigate the effects of functionally different compounds (agonist, partial agonist, and antagonist) on 5-HT receptor (5-HTR) occupancy and the associated hemodynamic responses. In anesthetized male nonhuman primates ( = 3), we used positron emission tomography (PET) imaging with the radioligand [C]AZ10419369 administered as a bolus followed by constant infusion to measure changes in 5-HTR occupancy. Simultaneously, we measured changes in cerebral blood volume (CBV) as a proxy of drug effects on neuronal activity. The 5-HTR partial agonist AZ10419369 elicited a dose-dependent biphasic hemodynamic response that was related to the 5-HTR occupancy. The magnitude of the response was spatially overlapping with high cerebral 5-HTR densities. High doses of AZ10419369 exerted an extracranial tissue vasoconstriction that was comparable to the less blood-brain barrier-permeable 5-HTR agonist sumatriptan. By contrast, injection of the antagonist GR127935 did not elicit significant hemodynamic responses, even at a 5-HTR cerebral occupancy similar to the one obtained with a high dose of AZ10419369. Given the knowledge we have of the 5-HTR and its function and distribution in the brain, the hemodynamic response informs us about the functionality of the given drug: changes in CBV are only produced when the receptor is stimulated by the partial agonist AZ10419369 and not by the antagonist GR127935, consistent with low basal occupancy by endogenous serotonin. We here show that combined simultaneous positron emission tomography and magnetic resonance imaging uniquely enables the assessment of CNS active compounds. We conducted a series of pharmacological interventions to interrogate 5-HT receptor binding and function and determined blood-brain barrier passage of drugs and demonstrate target involvement. Importantly, we show how the spatial and temporal effects on brain hemodynamics provide information about pharmacologically driven downstream CNS drug effects; the brain hemodynamic response shows characteristic dose-related effects that differ depending on agonistic or antagonistic drug characteristics and on local 5-HT receptor density. The technique lends itself to a comprehensive investigation and understanding of drugs' effects in the brain.

In vivo biased agonism at 5-HT1A receptors: characterisation by simultaneous PET/MR imaging

“…On the contrary, PET is able to quantify receptor occupancy by drugs at pharmacological doses, based on the competition with a specific radiotracer [18], without functional information. Simultaneous measurement of BOLD signal and receptor occupancy is therefore an attractive strategy to generate novel and critical information on the mechanism of action of CNS drugs and their neurovascular coupling [19][20][21][22][23]. In the context of biased agonism, it is theoretically possible to show that different agonists can stimulate different transduction pathways while binding on the same receptors, or even that they induce hemodynamic changes in different regions due to the stimulation of different subpopulations of receptors.…”

Advances in simultaneous PET/MR for imaging neuroreceptor function

“…Hansen et al. 15 used a partial agonist AZ-10419369 to investigate the functional consequences of activating the 5-HT 1B receptors. A dose-dependent effect of AZ10419369 on receptor occupancy (Figure 2) and a linear correlation between the drug dose and the peak changes in CBV was found.…”

“…Overall, pharmacological PET/MRI provides a platform for characterizing both existing and novel drugs. 14,15…”

Methods for Quantifying Neurotransmitter Dynamics in the Living Brain With PET Imaging

“…(B) 11 C-raclopride-PET binding potential maps (upper row) and CBV maps shown at peak value of the dynamic modeling term (Sander et al, 2015). (Hansen et al, 2017), demonstrating that biphasic functional signals can be linked to serotonin receptor occupancies. As an example of stimulus-based simultaneous PET/fMRI studies, the opioid pain system has been examined using 11 C-diprenorphine (Wey et al, 2014).…”

“…The effects of a partial serotonin receptor agonist have also been evaluated using simultaneous PET/fMRI ( Hansen et al, 2017 ), demonstrating that biphasic functional signals can be linked to serotonin receptor occupancies. As an example of stimulus-based simultaneous PET/fMRI studies, the opioid pain system has been examined using 11 C-diprenorphine ( Wey et al, 2014 ).…”