Functional characterization of 5-HT_1B receptor drugs in nonhuman primates using simultaneous PET-MR

TY - JOUR

T1 - Functional characterization of 5-HT1B receptor drugs in nonhuman primates using simultaneous PET-MR

AU - Hansen, Hanne D.

AU - Mandeville, Joseph B.

AU - Sander, Christin Y.

AU - Hooker, Jacob M.

AU - Catana, Ciprian

AU - Rosen, Bruce R.

AU - Knudsen, Gitte M.

PY - 2017/11

Y1 - 2017/11

N2 - 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-HT1B receptor (5-HT1BR) occupancy and the associated hemodynamic responses. In anesthetized male nonhuman primates (n = 3), we used positron emission tomography (PET) imaging with the radioligand [11C]AZ10419369 administered as a bolus followed by constant infusion to measure changes in 5-HT1BR occupancy. Simultaneously, we measured changes in cerebral blood volume (CBV) as a proxy of drug effects on neuronal activity. The 5-HT1BR partial agonist AZ10419369 elicited a dose-dependent biphasic hemodynamic response that was related to the 5-HT1BRoccupancy. The magnitude of the response was spatially overlapping with high cerebral 5-HT1BR densities. High doses of AZ10419369 exerted an extracranial tissue vasoconstriction that was comparable to the less blood– brain barrier-permeable 5-HT1BR agonist sumatriptan. By contrast, injection of the antagonist GR127935 did not elicit significant hemodynamic responses, even at a 5-HT1BRcerebral occupancy similar to the one obtained with a high dose of AZ10419369. Given the knowledge we have of the 5-HT1BR 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.

AB - 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-HT1B receptor (5-HT1BR) occupancy and the associated hemodynamic responses. In anesthetized male nonhuman primates (n = 3), we used positron emission tomography (PET) imaging with the radioligand [11C]AZ10419369 administered as a bolus followed by constant infusion to measure changes in 5-HT1BR occupancy. Simultaneously, we measured changes in cerebral blood volume (CBV) as a proxy of drug effects on neuronal activity. The 5-HT1BR partial agonist AZ10419369 elicited a dose-dependent biphasic hemodynamic response that was related to the 5-HT1BRoccupancy. The magnitude of the response was spatially overlapping with high cerebral 5-HT1BR densities. High doses of AZ10419369 exerted an extracranial tissue vasoconstriction that was comparable to the less blood– brain barrier-permeable 5-HT1BR agonist sumatriptan. By contrast, injection of the antagonist GR127935 did not elicit significant hemodynamic responses, even at a 5-HT1BRcerebral occupancy similar to the one obtained with a high dose of AZ10419369. Given the knowledge we have of the 5-HT1BR 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.

KW - 5-HT

KW - Nonhuman primates

KW - PET-MR imaging

KW - Pharmacology

U2 - 10.1523/jneurosci.1971-17.2017

DO - 10.1523/jneurosci.1971-17.2017

M3 - Journal article

C2 - 28972127

AN - SCOPUS:85032928969

SN - 0270-6474

VL - 37

SP - 10671

EP - 10678

JO - The Journal of neuroscience : the official journal of the Society for Neuroscience

JF - The Journal of neuroscience : the official journal of the Society for Neuroscience

IS - 44

ER -