Detection of benzodiazepine receptor occupancy in the human brain by positron emission tomography

Shinotoh, Hitoshi; Iyo, Masaomi; Yamada, Tatsuo; Ito, Osamu; Suzuki, Kazutoshi; Itoh, Takashi; Fukuda, Hiroshi; Yamasaki, Toshiro; Tateno, Yukio; Hirayama, Keizo

doi:10.1007/bf00442808

Cited by 49 publications

(22 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The regional localization of e IC]flumazenil was consistent with the regional rank order of eH]flu maze nil binding in vitro and with the results ob tained by other PET investigators (Persson et al, 1985(Persson et al, , 1989bMaloteaux et al, 1988;Pappata et al, 1988;Shinotoh et al, 1989). Images of the radioac tivity distribution, at three brain levels, for the vol unteer who was scanned three times in a single day are shown in Fig.…”

Section: Localization Of [ Ll C]flumazenilsupporting

confidence: 88%

Measurement of Benzodiazepine Receptor Number and Affinity in Humans Using Tracer Kinetic Modeling, Positron Emission Tomography, and [¹¹C]Flumazenil

Price

Mayberg

Dannals

et al. 1993

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Summary: Kinetic methods were used to obtain regional estimates of benzodiazepine receptor concentration Abbreviations used: BZ, benzodiazepine; CT, computed to mography; CV, coefficient of variation; PET, positron emission tomography; SA, specific activity. 656Method I. In Methods II and III , the ko./2/SA parameter was specifically constrained using the Method I value of kon and the volunteer's values Off2 and low SA (CillLmol) . Four parameters were determined simultaneously using Method II . In Method III, K/k2 was fixed to the inhibi tion value and only three parameters were estimated. Method I provided the most variable results and conver gence problems for regions with low receptor binding. Method II provided results that were less variable but very similar to the Method I results, without convergence problems . However, the K,lk2 ratios obtained by Method II ranged from 1.07 in the occipital cortex to 0.61 in the thalamus. Fixing the K,lk2 ratio in Method III provided a method that was physiologically consistent with the fixed value of f2 and resulted in parameters with considerably lower variability . The average Bmax values obtained using Method III were 100 ± 25 nM in the occipital cortex, 64 ± 18 nM in the cerebellum , and 38 ± 5.5 nM in the thal amus; the average Kd was 8.9 ± 1.0 nM (five brain re gions).

show abstract

Section: Localization Of [ Ll C]flumazenilsupporting

confidence: 88%

Measurement of Benzodiazepine Receptor Number and Affinity in Humans Using Tracer Kinetic Modeling, Positron Emission Tomography, and [¹¹C]Flumazenil

Price

Mayberg

Dannals

et al. 1993

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…Moreover, this occupancy is probably due to TPA023 rather than any metabolite(s) because the major metabolites (the isobutanol and NH-triazole) have very poor brain penetration (Atack, 2009). The extent of occupancy of benzodiazepine binding sites seen at either 0.032 (60 -70%) or 0.32 mg/kg (ϳ100%) TPA023 was much higher than that achieved in humans by using clinically relevant doses of lorazepam (6%) (LingfordHughes et al, 2005) or hypnotic doses of midazolam (Յ35%) (Malizia et al, 1996), diazepam (24%) (Pauli et al, 1991), clonazepam (15-24%) (Shinotoh et al, 1989), or zolpidem (21%) (Abadie et al, 1996). These data are consistent with .…”

Section: Downloaded Frommentioning

confidence: 99%

Reducing Abuse Liability of GABAA/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α1 and α2/3 Subtypes

Ator¹,

Atack

Hargreaves³

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Abuse-liability-related effects of subtype-selective GABA A modulators were explored relative to the prototypic benzodiazepine lorazepam. 7-Cyclobutyl-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo [4,3-b]pyridazine (TPA123) has weak partial agonist efficacy at ␣ 1 -, ␣ 2 -, ␣ 3 -, and ␣ 5 -containing GABA A receptors, whereas 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo [4,3-b]pyridazine (TPA023) has weaker partial agonist efficacy at ␣ 2 and ␣ 3 and none at ␣ 1 and ␣ 5 subtypes. For both compounds, preclinical data suggested efficacy as nonsedating anxiolytics. Self-injection of TPA123 (0.0032-0.1 mg/kg) and TPA023 (0.0032-0.32 mg/ kg) was compared with lorazepam (0.01-0.32 mg/kg) in baboons. TPA123 and lorazepam maintained self-injection higher than vehicle at two or more doses in each baboon; peak rate of self-injection of lorazepam was higher than TPA123. Self-injected lorazepam and TPA123 also increased rates of concurrently occurring food-maintained behavior. After the availability of self-administered TPA123 doses ended, an effect consistent with a mild benzodiazepine-like withdrawal syndrome occurred. In contrast with lorazepam and TPA123, TPA023 did not maintain self-administration. Positron emission tomography studies showed that TPA023 produced a dose-dependent inhibition in the binding of [ 11 C]flumazenil to the benzodiazepine binding site in the baboon, which was essentially complete (i.e., 100% occupancy) at the highest TPA023 dose (0.32 mg/kg). In a physical dependence study, TPA023 (32 mg/kg/24 h) was delivered as a continuous intragastric drip. Neither flumazenil at 14 days nor stopping TPA023 after 30 to 31 days resulted in the marked withdrawal syndrome characteristic of benzodiazepines in baboons. In the context of other data, elimination of efficacy at the ␣ 1 subtype of the GABA/benzodiazepine receptor is not sufficient to eliminate abuse liability but may do so when coupled with reduced ␣ 2/3 subtype efficacy.When they were introduced in the early 1960s, the benzodiazepines, typified by diazepam, represented a major advance in the treatment of generalized anxiety disorder relative to older treatments (Lader, 1993). They had a rapid onset of anxiolytic efficacy, were generally well tolerated, and relatively safe in overdose. Nevertheless, beginning in the late 1970s, concerns over the abuse potential and dependence liability of benzodiazepines resulted in more restrictive legislation (i.e., legal scheduling under the Controlled Substances Act in the United States in 1975 and by the World Health Organization in 1982) as well as a general reluctance of physicians to prescribe benzodiazepines (Williams and McBride, 1998). Benzodiazepines are abused by people who have a history of drug abuse, those on long-term benzodiazepines may independently escalate their dosage, patients can be overly reluctant to comply with physician recommendations to reduce benzodiazepine use, and there is considerable evidence of adverse ...

show abstract

“…occupies 15 to 23% BZ sites (Shinotoh et al, 1989), whereas sedative doses of diazepam (30 mg p.o.) and alprazolam (0.5 mg every 6 h) have respective occupancies of 24 and 16% (Pauli et al, 1991;Fujita et al, 1999).…”

Section: Occupancy Of Benzodiazepine Binding Sites By Tpa023 21mentioning

confidence: 99%

Benzodiazepine Binding Site Occupancy by the Novel GABAA Receptor Subtype-Selective Drug 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in Rats, Primates, and Humans

Atack

Wong

Fryer³

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

The GABA A receptor ␣2/␣3 subtype-selective compound 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo [4,3-b]pyridazine (TPA023; also known as MK-0777) is a triazolopyridazine that has similar, subnanomolar affinity for the benzodiazepine binding site of ␣1-, ␣2-, ␣3-, and ␣5-containing GABA A receptors and has partial agonist efficacy at the ␣2 and ␣3 but not the ␣1 or ␣5 subtypes. The purpose of the present study was to define the relationship between plasma TPA023 concentrations and benzodiazepine binding site occupancy across species measured using various methods. Thus, occupancy was measured using either in vivo 11 C]flumazenil PET in baboons and humans. For each study, plasma-occupancy curves were derived, and the plasma concentration of TPA023 required to produce 50% occupancy (EC 50 ) was calculated. The EC 50 values for rats, rhesus monkeys, and baboons were all similar and ranged from 19 to 30 ng/ml, although in humans, the EC 50 was slightly lower at 9 ng/ml. In humans, a single 2-mg dose of TPA023 produced in the region of 50 to 60% occupancy in the absence of overt sedative-like effects. Considering that nonselective full agonists are associated with sedation at occupancies of less than 30%, these data emphasize the relatively nonsedating nature of TPA023.The GABA A receptor is a pentameric assembly of subunits derived from a family of genes of which there are 19 members (␣1-6, ␤1-3, ␥1-3, ␦, ε, , , and 1-3), with the predominant composition of native receptors being ␣, ␤, and ␥ subunits, in a 2:2:1 stoichiometry and an ␣␤␣␤␥ arrangement as viewed from the synapse (Sieghart and Sperk, 2002

show abstract

Detection of benzodiazepine receptor occupancy in the human brain by positron emission tomography

Cited by 49 publications

References 26 publications

Measurement of Benzodiazepine Receptor Number and Affinity in Humans Using Tracer Kinetic Modeling, Positron Emission Tomography, and [¹¹C]Flumazenil

Measurement of Benzodiazepine Receptor Number and Affinity in Humans Using Tracer Kinetic Modeling, Positron Emission Tomography, and [¹¹C]Flumazenil

Reducing Abuse Liability of GABAA/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α1 and α2/3 Subtypes

Benzodiazepine Binding Site Occupancy by the Novel GABAA Receptor Subtype-Selective Drug 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in Rats, Primates, and Humans

Contact Info

Product

Resources

About

Detection of benzodiazepine receptor occupancy in the human brain by positron emission tomography

Cited by 49 publications

References 26 publications

Measurement of Benzodiazepine Receptor Number and Affinity in Humans Using Tracer Kinetic Modeling, Positron Emission Tomography, and [11C]Flumazenil

Measurement of Benzodiazepine Receptor Number and Affinity in Humans Using Tracer Kinetic Modeling, Positron Emission Tomography, and [11C]Flumazenil

Reducing Abuse Liability of GABAA/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α1 and α2/3 Subtypes

Benzodiazepine Binding Site Occupancy by the Novel GABAA Receptor Subtype-Selective Drug 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in Rats, Primates, and Humans

Contact Info

Product

Resources

About

Measurement of Benzodiazepine Receptor Number and Affinity in Humans Using Tracer Kinetic Modeling, Positron Emission Tomography, and [¹¹C]Flumazenil

Measurement of Benzodiazepine Receptor Number and Affinity in Humans Using Tracer Kinetic Modeling, Positron Emission Tomography, and [¹¹C]Flumazenil