National Institute on Drug Abuse (NIDA), Office of Acquisitions - Neurosciences, Station Support/Simplified Acquisitions, on behalf of the National Institute on Drug Abuse (NIDA) intends to negotiate and award a purchase order on a noncompetitive basis to the University of Massachusetts, Department of Chemistry, Amherst, MA, for conducting a project under the NIDA Scientific Director's Innovators Partnership Program, a novel and innovative pilot project undertaken by NIDA IRP investigators and extramural research collaborators. The project is entitled: Ligand-directed and photocleaveable fluorescent nanoprobes for the dopamine transporter.
A primary termination mechanism for dopamine signaling is through its reuptake from the synaptic cleft via the dopamine transporter (DAT). The DAT also serves in the uptake of psychostimulants such as methamphetamine to allow the intracellular blockade of vesicular monoamine transporters and the release of dopamine that is associated with the psychostimulant and euphoric actions of this drug of abuse. Moreover, cocaine binds to the DAT, blocking dopamine reuptake, which is the primary mechanism underlying its abuse potential that can lead to addiction. Elucidation of the structure and function of the DAT protein and their constituitive roles in the brain as well as the long-term consequences of chronic drug taking is essential for developing novel treatment strategies. The period of performance is 12 months.
An approach that might be employed to help decipher the locations and trafficking of the DAT would be to build a ligand-directed and photocleaveable fluorescent nanoprobe. Recently, an academic research group designed and synthesized a very clever tri-functional molecule that used a polyamine-based ligand to direct a fluorescent probe to AMPA receptors. This probe was directly attached to a photocleavable functional group that in turn was attached to both an electrophile (Michael acceptor) and a fluorophore. This research group demonstrated that the polyamine directed this nanoprobe to AMPA receptors where it covalently attached to the receptor protein. Upon photolysis, the polyamine was released and the protein remained fluorescently labeled, now without a small molecule covalently attached. The NIDA proposest to use this approach with our tropane-based DAT ligand, MFZ 2-12, various fluorescent ligands for optimal visualization, including a pH-sensitive fluorescent reagent to create a DAT-directed fluorescent ligand that will allow the DAT to be fluorescently labeled and ultimately provide an open binding site for interaction with drug molecules to study their effects on translocation and post-endocytotic processes. The NIDA expects that many more applications of these nanoprobes as well as an expansion toward other target proteins will be the long-range goal of this project and propose the design, synthesis and initial characterization of these new tools herein.
The academic lab that produced the AMPA receptor-directed probe will provide the NIDA with an advanced precursor that will be employed in a synthetic route as outlined in the proposal. In short, the academic lab will produce this intermediate and will ship the material to the NIDA. Collaboration with the synthetic academic lab as well as the imaging lab will be the key to success of the proposed studies. The synthetic lab has the expertise in developing this advanced intermediate and the imaging lab has the imaging expertise. The NIDA has the expertise in the structure-activity relationship of the DAT and the NIDA has published extensively on this subject.
This acquisition is being conducted under Simplified Acquisition Procedures using FAR 12 procedures, and is exempt from competition requirements in FAR Part 6. The determination by the Government not to compete the proposed contract based upon responses to this notice is solely within the discretion of the Government. Comments to this announcement, referencing the solicitation number, may be submitted prior to the closing date of this announcement to the NIDA SS/SA Branch electronically to the attention of Susan Nsangou, Contracting Officer at [email protected].