| title: |
Kinetic mechanism of ligand interaction with dopamine transporter and its implications on brain imaging |
| reg no: |
ETF6698 |
| project type: |
Estonian Science Foundation research grant |
| subject: |
1.7. Organic Chemistry and Biochemistry
|
| status: |
accepted |
| institution: |
TU Faculty of Physics and Chemistry |
| head of project: |
Jaak Järv |
| duration: |
01.01.2006 - 31.12.2009 |
| description: |
Labeling of dopamine transporter (DAT) by specific ligands is used for tracing dopaminergic nerve terminals in brain by PET and SPECT analysis. These ligands (transporter inhibitors) should interact with their target sites very effectively and there are indications that their binding is accompanied by a conformational transition of the protein, yielding the “isomerised” DAT-ligand complex. In this study kinetics of interaction of selective DAT tracer 3H-PE2I with the transporter protein is studied to differentiate between the binding and “isomerization” steps and to characterize the mechanism of this process in terms of the appropriate kinetic model. Further the kinetic approach, using 3H-PE2I as “reporter” ligand, will be extended to analyze the mechanism of binding of other dopaminergic ligands with DAT, including the putative metabolites of PE2I formed in brain. The results will have implication on pharmacokinetic modeling of the tracer activity in PET and SPECT as well as for amendment of the drug design methods based on quantitative structure-activity analysis. On the basis of the results obtained synthetic schemes for these new ligands will be worked out. |