PET imaging studies measuring the change in dopamine D2-class of receptors function have historically used radiotracers that are not capable of discriminating between D2/ and D3 receptors. For example, [11C] raclopride, [18F] fallypride and [11C] PHNO bind with high affinity to dopamine D2 and D3 receptors. Therefore, measurement of "D2 receptor binding potential" obtained with these radiotracers consists of a composite of D2 and D3 receptor density. A number of studies have provided evidence suggesting that D2 and D3 receptors are regulated in an opposing manner in a variety of CNS disorders. For example, it has been reported that there is a 45% reduction in D3 receptors in the ventral striatum and a 15% increase in D2 receptors the caudate/putamen of postmortem brain samples of Parkinson's Disease. Other studies have shown an increase in D3 receptors and a decrease in D2 receptors in brain samples obtained following chronic exposure to cocaine. Therefore, the development of radiotracers having a high affinity for D3 versus D2 receptors, and vice versa, would be of tremendous interest to the PET imaging and neuroscience research community since it would enable the independent measurement of D2 and D3 receptors in a variety of CNS disorders. Our group is currently funded (through PA-03-112) to develop PET radiotracers having a high affinity and selectivity for D2 versus D3 receptors. The function of the current research project is to develop PET radiotracers selective for the D3 receptor which would complement our ongoing research in the development of D2-selective radiotracers. The ultimate goal of our research effort is to develop a novel strategy for imaging the change in D3 and D2 receptors in a variety of CNS disorders.
An alteration in the function of the dopamine D3 receptor is thought to play a key role in a variety of pathological conditions including schizophrenia, Parkinson's Disease, Alzheimer's Disease, and drug abuse. However, the precise role of this receptor in these brain disorders is currently not known. The goal of the research described in this grant is to develop novel probes for imaging the D3 receptor in the living human brain with the functional imaging technique Positron Emission Tomography or PET. These probes are expected to provide valuable information on the role of the D3 receptor in disorders of the central nervous system.
|Reilly, Sean W; Mach, Robert H (2016) Pd-Catalyzed Synthesis of Piperazine Scaffolds Under Aerobic and Solvent-Free Conditions. Org Lett :|
|Peng, Xin; Wang, Qi; Mishra, Yogesh et al. (2015) Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands. Bioorg Med Chem Lett 25:519-23|
|Rangel-Barajas, Claudia; Malik, Maninder; Taylor, Michelle et al. (2014) Characterization of [(3) H]LS-3-134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand. J Neurochem 131:418-31|
|Li, Aixiao; Mishra, Yogesh; Malik, Maninder et al. (2013) Evaluation of N-phenyl homopiperazine analogs as potential dopamine D3 receptor selective ligands. Bioorg Med Chem 21:2988-98|
|Sun, Jianjun; Kouranova, Evguenia; Cui, Xiaoxia et al. (2013) Regulation of dopamine presynaptic markers and receptors in the striatum of DJ-1 and Pink1 knockout rats. Neurosci Lett 557 Pt B:123-8|
|Sun, J; Cairns, N J; Perlmutter, J S et al. (2013) Regulation of dopamine Dâ‚ƒ receptor in the striatal regions and substantia nigra in diffuse Lewy body disease. Neuroscience 248:112-26|
|Tu, Zhude; Li, Shihong; Li, Aixiao et al. (2013) Synthesis and in vitro pharmacological evaluation of indolyl carboxylic amide analogues as D3 dopamine receptor selective ligands. Medchemcomm 4:1283-1289|
|Sun, Jianjun; Xu, Jinbin; Cairns, Nigel J et al. (2012) Dopamine D1, D2, D3 receptors, vesicular monoamine transporter type-2 (VMAT2) and dopamine transporter (DAT) densities in aged human brain. PLoS One 7:e49483|
|Tu, Zhude; Li, Shihong; Cui, Jinquan et al. (2011) Synthesis and pharmacological evaluation of fluorine-containing Dâ‚ƒ dopamine receptor ligands. J Med Chem 54:1555-64|
|Mach, Robert H; Tu, Zhude; Xu, Jinbin et al. (2011) Endogenous dopamine (DA) competes with the binding of a radiolabeled Dâ‚ƒ receptor partial agonist in vivo: a positron emission tomography study. Synapse 65:724-32|
Showing the most recent 10 out of 12 publications