D_SOW_Ex-vivo occupancy.pdf
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- Attached to
- Full Saturation Radiography Study for One Compound Federal contract opportunity
- Solicitation number
- 75N95021Q00227
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| D_FAR_52.204-26_Oct_2020.pdf | ||
| D_VAS Worksheet.pdf | ||
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9.0.0.2.20101008.1.734229 Statement of Work for Services (SOW) General Information:
Title of Project:
Statement of Need and Purpose:
Background Information and Objective:
Period of Performance:
Scope of Work:
General Requirements:
Independently and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government as needed to perform the Statement of Work below:
Specific Requirements:
Level of Effort:
Government Responsibilities:
Delivery or Deliverables:
Reporting Requirements:
Other Considerations:
Travel:
Key Personnel:
Information System Security Plan:
Data Rights:
Section 508:
Publications and Publicity:
Confidentiality of Information:
Full Saturation Radiography Study for One Compound.
To evaluate receptor occupancy of one D3 selective antagonist via ex-vivo platform using 3H-PHNO as D3-selective radio labeled ligand.
The biogenic amine dopamine is an essential neurotransmitter in the brain and periphery. The cerebral dopaminergic system is implicated in a variety of physiological and pathophysiological processes. It comprises the regulation of motion, emotion and cognition. An imbalance in the dopaminergic neurotransmission and dopamine receptors underlies manifold neurological and psychiatric disorders. All drugs of abuse either directly or indirectly increase dopamine levels in the mesolimbic regions of the brain. The dopamine receptor subtype D3 is localized in the key neurocircuits that underlie motivation and cognition, and in contrast to D2R do not appear to play a major role in movement. Hence D3R has been proposed as a promising target for development of psychostimulant addiction and relapse pharmacotherapy. Also, seminal reports have shown increased D3R subtype in the basal ganglia in post-mortem brains of cocaine and methamphetamine overdose victims using PET studies thus further validating this approach.
TRND at NCATS in collaboration with the investigators at NIDA has emabarked on a journey to find novel D3R antagonists while displaying significant selectivity from the highly homologous D2 receptors. Working on the bitopic ligands identified by earlier inevstigations, the team has identified several lead chemotypes that display around a 500 fold selectivity over D2R in the binding assays. These lead molecules occupy an orthosteric binding site (OBS) at D3R and also connect to a secondary binding pocket (SBP), via a 4 carbon linker, responsible for achieving selectivity amongst the dopamine receptor subtypes. The lead molecules from different chemotype series, identified by the team are being considered for development.
Towards a successful translation of these lead molecules and to study pharmacodynamics of these compounds, the team has proposed ex-vivo and in-vivo receptor occupancy studies in Sprague Dawley rats.
In this study, we will determine the occupancy of a known D3 selective antagonist in D3 receptor rich regions of the brain. We will also be looking at the D2 receptor regions to evaluate the in-vivo selectivity of the antagonist. We plan to exploit the differential localization of D2 and D3 receptors in the rat striatum, Substantia Nigra, Ventral Tegmental Area, Olfactory tubercle, and Cerebellum lobes 9 and 10 in this study. While Substantia Nigra, VTA, OT and Cerebellar lobes 9 and 10 have been shown to be rich in D3R receptor expression, the receptor binding in the striatum can serve as the D2 rich control. Three different concentrations of D3 antagonist will be used in the study and a subsequent tail vein IV injection of 3H-PHNO will be performed after a set time to measure the occupancy of the D3 antagonist in the above mentioned brain regions. Vehicle dosing will serve as a control for 3H-PHNO occupancy.
The period of performance is 6-8 weeks from the date of contract award.
1) Naïve rodents shall be sourced for this study (n=12).
2) Single compound assay (4 groups, 3 rats per group):
i. Vehicle + 3 concentrations candidate compound
3) Animals shall receive an IP or PO injection of vehicle/compound (dose route and concentrations to be finalized later).
4) After injection of vehicle/compound, animals shall receive an IV injection of [3H]PHNO (dose to be finalized later).
5) At a single time point post-[3H]PHNO dosing, animals shall be exsanguinated, and their brains shall be harvested and fresh-frozen.
6) Brains shall be sectioned coronally on a cryostat (10-20 μm thickness) from anterior to posterior to include several regions of interest (typically prefrontal cortex, striatum, hippocampus, and cerebellum).
7) Sections shall be apposed to a tritium-sensitive phosphoimaging plate alongside a tissue-equivalent microscale for expression of binding as fmol/mg tissue.
8) For quantification, regions of interest shall be drawn on up to 3 areas.
9) Delivery of the ex vivo dose occupancy assay shall consist of binding (fmol/mg tissue) of [3H]PHNO in the compound dosed tissues expressed as a percentage of total binding (vehicle dose) for each of the regions of interest.
N/A NCATS will provide the compounds for the study.
The contractor shall complete the work within 6-8 weeks from receipt of compounds.
The contractor shall provide the results of the study to NCATS through a written report.
N/A N/A
N/A The right to all data belongs to NCATS.
N/A The results of the study will not be published at the moment.
Any information provided to the contractor by NCATS or collected by the contractor on behalf of NCATS shall be used only for the purpose of carrying out the provisions of this contract and shall not be disclosed or made known in any manner to any persons except as may be necessary in the performance of the contract
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