In Vivo High Intrinsic Efficacy of Triazolam: A Positron Emission Tomography Study in Nonhuman Primates

Abstract

The triazolobenzodiazepine triazolam is a central‐type benzodiazepine receptor (BZR) ligand that is widely prescribed as a hypnotic agent. Triazolam produces its effects through potentiation of γ‐aminobutyric acid‐mediated neurotransmission. Findings reported from in vitro binding studies showed some discrepancies concerning the pharmacological characteristics of triazolam. The present study aims to characterize in vivo the biochemical properties of triazolam, i.e., cerebral pharmacokinetics, interaction with BZR, potency, and intrinsic efficacy. Triazolam was studied in living nonhuman primates using positron emission tomography. Two different studies were carried out: (a) a direct study using [11C]triazolam and (b) an indirect competition study using the radiolabeled BZR antagonist [11C]flumazenil. Results showed that, in the brain in vivo, triazolam binds specifically and competitively to the BZR. Its rapid cerebral kinetics is consistent with a hypnotic profile (maximal binding after 23 min, elimination half‐life of 202 min). Triazolam is very potent in displacing [11C]flumazenil (ID50= 28 ± 6 μg/kg). Hill analysis of the displacement curve does not show obvious binding‐site heterogeneity. Triazolam is 20 times more potent in displacing [11C]flumazenil and 50 times more potent in inhibiting pentylenetetrazol‐induced paroxysmal activity than the full benzodiazepine agonist diazepam. Interestingly, the simultaneous use of positron emission tomography and EEG recording allowed us to show that triazolam‐positive intrinsic efficacy is slightly higher (20%) than that of diazepam. An attractive hypothesis proposes that the severity of side effects of BZR ligands is proportional to their intrinsic efficacy. Therefore, our study shows that triazolam side effects, as for other benzodiazepines, may be related to its high intrinsic efficacy in vivo.

GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans

“…More recently, for the partial GABA A receptor agonists MRK-409 and TPA023, sedation has been reported at a broad range of receptor occupancy, from severe sedation at <10% occupancy (MRK-409) or lack of overt sedation up to 50% receptor occupancy (TPA023) (Atack et al 2010, 2011a,b). One possible explanation for this broad range of tolerated levels of GABA A receptor occupancy of novel partial GABA A receptor agonists may be their intrinsic activity as suggested in the early studies comparing GABA A receptor modulators (Bottlaender et al 1994). …”

PET radioligands targeting the brain GABAA/benzodiazepine receptor complex

“…Triazolam, a more potent agonist and structural analogue of alprazolam, was also labeled in a similar fashion (Scheme ). [ 11 C]triazolam was investigated in nonhuman primates showing rapid uptake of the radioligand into brain reaching a maximum at 20 min followed by slow clearance ( t 1/2 = 202 min). Specific binding was partly displaceable by triazolam, flumazenil, and zolpidem.…”

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

“…Aside from its obvious utility for comparative anatomy of the mGlu 5 receptor distribution in vivo, having an mGlu 5 receptor ligand such as 11 C-ABP688 also presents the possibility to conduct blocking and competition studies in vivo similarly to work that has been conducted on other receptors, i.e., NMDA (Ametamey et al 1999), benzodiazepine (Bottlaender et al 1994;Lingford-Hughes et al 2002), and dopamine (Kassiou et al 2002;Nikolaus et al 2005) receptors. By circumventing the need to radiolabel each novel compound, competition and blocking studies can considerably speed imaging studies with new compounds.…”