Anti-stress effects of ONO-2952, a novel translocator protein 18 kDa antagonist, in rats

Mitsui, Katsukuni; Niwa, Tomohiro; Kawahara, Yuji; Morimoto, Noriko; Ohmoto, Kazuyuki; Kato, Masashi; Yamaura, Yoshiyuki; Yoshimoto, Noriko; Suna, Hideaki; Katsumata, Seishi

doi:10.1016/j.neuropharm.2015.07.011

Cited by 19 publications

(24 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The K i value derived via displacement of [ 3 H]PK11195 TSPO‐binding using increasing concentrations of ONO‐2952 in mitochondrial membrane fractions prepared from rat whole brains was 0.330 nM (0.132 ng/ml) and a TSPO occupancy of approximately 50% was observed in cerebral cortex and hippocampus at an unbound plasma concentration of 0.158–0.205 nM (mean plasma concentration of 6.30 ng/ml, including protein bound and free drug, protein binding in rat: 98.7–99.0%) in the brain of restraint stressed rats (Mitsui et al, ). In humans the plasma protein binding of ONO‐2952 is 99.8%, thus if the K i of 34.1 nM is corrected to take into account only the unbound concentration of ONO‐2952 (i.e., concentration free to equilibrate across the BBB), this corresponds to a K i of 0.068 nM.…”

Section: Discussionmentioning

confidence: 99%

“…Antagonism of TSPO by ONO‐2952 inhibits restraint stress‐induced production of the neurosteroid precursor pregnenolone in the hippocampus and norepinephrine release in the amygdala in rats, and thus may normalize the balance of excitatory and inhibitory neurotransmission (Mitsui et al, ). Furthermore, ONO‐2952 has been shown to reduce stress‐induced defecation and freezing behavior in a rat conditioned fear stress model (Mitsui et al, ). This study sought to confirm the binding of ONO‐2952 to brain TSPO and to evaluate brain TSPO occupancy and its relationship with ONO‐2952 plasma concentration.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [¹¹C]PBR28

Frankle

Narendran

Wood

et al. 2017

Synapse

Self Cite

View full text Add to dashboard Cite

ONO-2952, a novel antagonist of translocator protein 18 kDa (TSPO), binds with high affinity to TSPO in rat brain and human tumor cell line membrane preparations. This study used the TSPO-specific PET radioligand [ C]PBR28 to confirm binding of ONO-2952 to brain TSPO in human subjects, and evaluate brain TSPO occupancy and its relationship with ONO-2952 plasma concentration. Sixteen healthy subjects received a single oral dose of 200, 60, 20, or 6 mg ONO-2952 (n = 4 per dose). Two PET scans with [ C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO-2952 administration. [ C]PBR28 regional distribution volume (V ) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (V ) was obtained on an individual basis for each subject using linear regression as the x-intercept of the Lassen plot. The binding potential relative to V (BP ) was derived as the difference between V in the ROI (V ROI) and V , normalized to V ; BP = (V ROI - V )/V . TSPO occupancy was calculated as the change in BP (ΔBP ) from individual's baseline scan to the on-medication scan to the baseline BP value. TSPO occupancy by ONO-2952 was dose dependent between 20-200 mg, approaching saturation at 200 mg both in the whole brain and in 15 anatomic regions of interest (ROI). Estimated K values ranged from 24.1 to 72.2 nM. This open-label, single-center, single-dose study demonstrated engagement of ONO-2952 to brain TSPO. The relationship between pharmacokinetics and TSPO occupancy observed in this study support the hypothesis that ONO-2952 could potentially modulate neurosteroid production by binding to brain TSPO.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [¹¹C]PBR28

Frankle

Narendran

Wood

et al. 2017

Synapse

Self Cite

View full text Add to dashboard Cite

show abstract

“…It decreased visceral hypersensitivity in animal models. [32] In a 4-week study in IBS-D with approximately 65 patients per arm, ONO-2952 (60 mg) tended to improve stool consistency and diarrhea, but effects were not statistically significant versus placebo. [33]…”

Section: Diarrhea and Diarrhea-predominant Ibs (Ibs-d)mentioning

confidence: 99%

Existing and emerging therapies for managing constipation and diarrhea

Bharucha

Wouters

Tack

2017

Current Opinion in Pharmacology

View full text Add to dashboard Cite

Functional bowel disorders (i.e., constipation and diarrhea) are characterized by abdominal pain, bloating, distention, and/or bowel habit abnormalities in the absence of obvious anatomic or physiologic abnormalities on routine diagnostic tests. These symptoms are attributable to gastrointestinal sensorimotor dysfunctions resulting from peripheral and/or central mechanisms. Available drugs target the underlying bowel disturbance (ie, constipation, diarrhea, or both), supplemented when necessary by management of pain. Osmotic and stimulant laxatives, secretagogues, and serotonin 5-HT4 receptor agonists are approved for treating constipation. Loperamide, anticholinergic agents, rifaximin, bile-acid binding agents, eluxadoline, and clonidine are used to treat diarrhea. Several exciting new compounds, some of which have been evaluated in humans, are currently under development.

show abstract

“…ONO-2952 is a novel and selective inhibitor of TSPO that reduces stressinduced defecation and visceral hyperalgesia in rat models (80).…”

Section: Ibs-c (79)mentioning

confidence: 99%

Experimental Models of Irritable Bowel Syndrome and the Role of the Enteric Neurotransmission

Vannucchi

Evangelista

2017

Preprint

View full text Add to dashboard Cite

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal diseases in humans. It is characterized by visceral pain and/or discomfort, hypersensitivity and abnormal motor responses along with change in gut habits. Although the etiopathogenesis of IBS is only partially understood, a main role has been attributed to psychosocial stress of different origin. Animals models such as neonatal maternal separation, water avoidance stress and wrap restraint stress have been developed as psychosocial stressors in the attempt to reproduce the IBS symptomatology and identify the cellular mechanisms responsible for the disease. The study of these models has led to the production of drugs potentially useful for IBS treatment. This review intends to give an overview on the results obtained with the animal models; to emphasize the role of the enteric nervous system in IBS appearance and evolution and as a possible target of drug therapies.

show abstract

Anti-stress effects of ONO-2952, a novel translocator protein 18 kDa antagonist, in rats

Cited by 19 publications

References 60 publications

Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [¹¹C]PBR28

Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [¹¹C]PBR28

Existing and emerging therapies for managing constipation and diarrhea

Experimental Models of Irritable Bowel Syndrome and the Role of the Enteric Neurotransmission

Contact Info

Product

Resources

About

Anti-stress effects of ONO-2952, a novel translocator protein 18 kDa antagonist, in rats

Cited by 19 publications

References 60 publications

Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [11C]PBR28

Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [11C]PBR28

Existing and emerging therapies for managing constipation and diarrhea

Experimental Models of Irritable Bowel Syndrome and the Role of the Enteric Neurotransmission

Contact Info

Product

Resources

About

Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [¹¹C]PBR28

Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [¹¹C]PBR28