The Vasopressin V<sub>1b</sub>Receptor Antagonist SSR149415 in the Treatment of Major Depressive and Generalized Anxiety Disorders

Griebel, Guy; Beeské, Sandra; Stahl, Stephen M.

doi:10.4088/jcp.12m07804

Cited by 70 publications

(39 citation statements)

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“…TASP0390325 is a pyridopyrimidin-4-one derivative, and its interference with 11 C-TASP699 binding was predicted on a structural basis. Unlike these chemicals, TASP0233278 has an indolin-2-one core structure and is structurally similar to SSR149415 (12), a V 1B R antagonist that has been examined in clinical trials (15). Although the development of SSR149415 has been halted, our results justify the use of 11 C-TASP699 PET for in vivo assessments of the relationships between receptor occupancies by SSR149415 at clinically applied doses and its pharmacologic effects.…”

Section: Discussionmentioning

confidence: 76%

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High-Contrast PET Imaging of Vasopressin V_1B Receptors with a Novel Radioligand, ¹¹C-TASP699

et al. 2017

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Vasopressin 1B receptors (V 1B Rs) are abundantly expressed in the pituitary, and in vivo PET of V 1B Rs was recently enabled by our development of a specific radioligand, 11 C-TASP0434299, derivatized from pyridopyrimidin-4-one. Here, we identified a novel pyridopyrimidin-4-one analog, N-tert-butyl-2-[2-(6-11 C-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido [2,3-d]pyrimidin-3(4H)-yl]acetamide ( 11 C-TASP0410699, hereafter referred to as 11 C-TASP699), as a potent V 1B R radioligand producing a higher image contrast for the target than 11 C-TASP0434299. Methods: In vitro properties of TASP699 were assessed by assaying its affinity for human V 1B R and its selectivity for offtarget molecules. Radioactive uptake in the pituitary was analyzed using PET in rhesus monkeys after intravenous administration of 11 C-TASP699., were administered before the radioligand injection. Autoradiographic labeling of monkey pituitary slices with 11 C-TASP699 was conducted with or without nonradioactive V 1B R antagonists. Results: The half maximal inhibitory concentration (IC 50 ) of TASP699 for human V 1B Rs (0.165 nM) was lower than that of TASP0434299 (0.526 nM), whereas its IC 50 values for off-target molecules exceeded 1 mM. PET imaging in monkeys demonstrated that the peak pituitary uptake of 11 C-TASP699 was almost equivalent to that of 11 C-TASP0434299 and that pretreatment with TASP0390325 inhibited the retention of 11 C-TASP699 in a dose-dependent manner, inducing nearly full occupancy at 0.3 mg/kg. Specific radioligand binding was determined as a specific-to-nondisplaceable uptake ratio at equilibrium using radioactivity retentions at 60 min in baseline and blocking studies. This ratio for 11 C-TASP699 was approximately 2.5-fold greater than that of 11 C-TASP0434299. A reversed-phase high-performance liquid chromatography study identified the parent and polar radiometabolites. Affinities of 2 predicted metabolite candidates for V 1B Rs were more than 10 times weaker than that of the parent. Intense autoradiographic labeling of the anterior pituitary with 11 C-TASP699 was inhibited with TASP0390325 in a concentration-dependent manner. Conclusion: 11 C-TASP699 yielded PET images of pituitary V 1B Rs with a higher contrast than 11 C-TASP0434299, supporting the applicability of 11 C-TASP699 in the assessment of neuropsychiatric diseases and dose findings for test drugs in clinical trials. Ar ginine vasopressin (AVP) is an endogenous cyclic nonapeptide that is mainly synthesized in the hypothalamus and is involved in diverse physiologic functions, which are triggered by the activation vasopressin 1A (V 1A ), 1B, and 2 (V 2 ) receptors and oxytocin receptors (1-5).Of these, the V 1B receptor (V 1B R) is expressed abundantly in the anterior pituitary (6-8), and its activation leads to the secretion of adrenocorticotropic hormones from corticotrophs, which play a pivotal role in stress responses through the modulation of the hypothalamic-pituitary-adrenal axis (9,10). V 1B R antagonists have been reported to show...

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Section: Discussionmentioning

confidence: 76%

“…V 1B R antagonists have been reported to show pharmacologic actions in animal models (11)(12)(13)(14), whereas the effectiveness of V 1B R antagonists in humans has yet to be clarified (15,16). It is accordingly required to demonstrate and quantify the target engagement of test compounds to the V 1B R to determine appropriate doses for clinical efficacy.…”

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confidence: 99%

High-Contrast PET Imaging of Vasopressin V_1B Receptors with a Novel Radioligand, ¹¹C-TASP699

et al. 2017

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“…Furthermore, Avpr 1b antagonists showed promising results against anxiety in clinical trials (Griebel et al, 2002). Unfortunately, subsequent results came up disappointing (Griebel et al, 2012). On their side, the expression of NK 3 Rs in human hypothalamus (Chawla et al, 1997) as well as anxiolytic effects following central injection of NK 3 R agonists in rats and mice (Ribeiro et al, 1999;Schable et al, 2011) target NK 3 R-related drugs as potential new treatment against stress-related disorders.…”

Section: Resultsmentioning

confidence: 99%

Stress-induced dendritic internalization and nuclear translocation of the neurokinin-3 (NK3) receptor in vasopressinergic profiles of the rat paraventricular nucleus of the hypothalamus

2014

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“…These results indicate that [ 11 C]TASP0434299 enables visualizing the V 1B receptor in the pituitary noninvasively, and would help in quantifying the V 1B receptor. This utility would be of particular significance in a receptor occupancy study, which would help to determine the optimal doses of V 1B receptor antagonists for clinical trials (Griebel et al, 2012;Katz et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

TASP0434299: A Novel Pyridopyrimidin-4-One Derivative as a Radioligand for Vasopressin V1B Receptor

Koga

Yoshinaga

Uematsu

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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3 H]TASP0434299 can be used as an in vivo radiotracer to measure the occupancy of the V 1B receptor. Finally, the intravenous administration of [ 11 C]TASP0434299 provided positron emission tomographic images of the V 1B receptor in the pituitary in an anesthetized monkey, and the signal was blocked by pretreatment with an excess of unlabeled TASP0434299. These results indicate that radiolabeled TASP0434299 is the first radioligand to be capable of quantifying the V 1B receptor selectively in both in vitro and in vivo studies and will provide a clinical biomarker for determining the occupancy of the V 1B receptor during drug development or for monitoring the levels of the V 1B receptor in diseased conditions.

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The Vasopressin V_1bReceptor Antagonist SSR149415 in the Treatment of Major Depressive and Generalized Anxiety Disorders

Abstract: ClinicalTrials.gov identifiers: NCT00374166 (Sanofi ID number: DFI5880), NCT00361491 (Sanofi ID number: DFI5879), NCT00358631 (Sanofi ID number: DFI5878), NCT01606384 (Sanofi ID number: PDY5467).

Cited by 70 publications

References 20 publications

High-Contrast PET Imaging of Vasopressin V_1B Receptors with a Novel Radioligand, ¹¹C-TASP699

High-Contrast PET Imaging of Vasopressin V_1B Receptors with a Novel Radioligand, ¹¹C-TASP699

Stress-induced dendritic internalization and nuclear translocation of the neurokinin-3 (NK3) receptor in vasopressinergic profiles of the rat paraventricular nucleus of the hypothalamus

TASP0434299: A Novel Pyridopyrimidin-4-One Derivative as a Radioligand for Vasopressin V1B Receptor

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The Vasopressin V1bReceptor Antagonist SSR149415 in the Treatment of Major Depressive and Generalized Anxiety Disorders

Abstract: ClinicalTrials.gov identifiers: NCT00374166 (Sanofi ID number: DFI5880), NCT00361491 (Sanofi ID number: DFI5879), NCT00358631 (Sanofi ID number: DFI5878), NCT01606384 (Sanofi ID number: PDY5467).

Cited by 70 publications

References 20 publications

High-Contrast PET Imaging of Vasopressin V1B Receptors with a Novel Radioligand, 11C-TASP699

High-Contrast PET Imaging of Vasopressin V1B Receptors with a Novel Radioligand, 11C-TASP699

Stress-induced dendritic internalization and nuclear translocation of the neurokinin-3 (NK3) receptor in vasopressinergic profiles of the rat paraventricular nucleus of the hypothalamus

TASP0434299: A Novel Pyridopyrimidin-4-One Derivative as a Radioligand for Vasopressin V1B Receptor

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The Vasopressin V_1bReceptor Antagonist SSR149415 in the Treatment of Major Depressive and Generalized Anxiety Disorders

High-Contrast PET Imaging of Vasopressin V_1B Receptors with a Novel Radioligand, ¹¹C-TASP699

High-Contrast PET Imaging of Vasopressin V_1B Receptors with a Novel Radioligand, ¹¹C-TASP699