510-74-7Relevant academic research and scientific papers
Target-specific ligands and gadolinium-based complexes for imaging of dopamine receptors: Synthesis, binding affinity, and relaxivity
Zigelboim, Isaac,Weissberg, Avi,Cohen, Yoram
, p. 7001 - 7012 (2013/08/23)
Magnetic resonance imaging (MRI) and positron emission tomography (PET) are two extremely important imaging modalities with unlimited tissue penetration. Molecular imaging is a field by which specific targets or biological processes are imaged. MRI, which is used for functional imaging and for the diagnosis of a broad range of pathologic conditions, suffers from limited specificity and intrinsically low sensitivity. One possibility to alleviate partially these limitations is to use contrast agents (CAs) and more importantly target-specific CAs. We have developed a modular synthesis of novel ligands and gadolinium(III)-based target-specific MRI CAs with high relaxivity and high binding affinity toward the dopamine receptors. The prepared ligands and MRI CAs are based on spiperone as targeting moiety. The prepared target-specific CAs can potentially be used for in vitro and possibly in vivo MR imaging of dopaminergic receptors. Importantly the ligands prepared using the modular approach presented in this paper may also be useful for other imaging modalities such as PET (or SPECT) by just replacing, at the last stage of the synthesis, the gadolinium cation by other metal cations having relatively long half-lives, such as 64Cu, 89Zr, 11In, and more.
Antagonism of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane stimulus with a newly identified 5-HT2- versus 5-HT(1C)-selective antagonist
Ismaiel,De los Angeles,Teitler,Ingher,Glennon
, p. 2519 - 2525 (2007/10/02)
DOM [i.e., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane] is a 5- HT(1C/2) serotonin agonist that exerts stimulus control of behavior in animals. In order to determine if the discriminative stimulus effect of DOM is 5-HT(1C)- or 5-HT2-mediated, it would be informative to conduct tests of stimulus antagonism with a 5-HT(1C)- or 5-HT2-selective antagonist. To date, no such agents exist. Although the neuroleptic agent spiperone binds at D2 dopamine receptors and 5-HT(1A) serotonin receptors, (a) it displays about a 1000-fold selectivity for 5-HT2 versus 5-HT(1C) sites and (b) it has been used as a '5-HT2-selective' antagonist. Because spiperone is a behaviorally disruptive agent, it is not suitable for use in drug-discrimination studies. Using the spiperone molecule as a starting point, a limited structure- affinity investigation was conducted in order to identify a suitable antagonist with high affinity and selectivity for 5-HT2 receptors, and yet an antagonist that might lack the disruptive actions of spiperone. Various modifications of the spiperone molecule were examined, but most resulted in decreased 5-HT2 affinity or in loss of selectivity. One compound, 8-[3-(4- fluorophenoxy)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (26), was shown to bind at 5-HT2 sites with high affinity (K(i) = 2 nM) and >2,000- fold selectivity versus 5-HT(1C) sites. In tests of stimulus antagonism using rats trained to discriminate 1 mg/kg of DOM from saline vehicle, 26 behaved as a potent antagonist (ED50 = 0.003 mg/kg) and lacked the disruptive effects associated with spiperone. As such, (a) it would appear that the DOM stimulus is primarily a 5-HT2-mediated, and not 5-HT(1C)-mediated, phenomenon, and (b) compound 26 may find application in other pharmacologic investigations where spiperone may not be a suitable antagonist.
