56743-03-4Relevant academic research and scientific papers
Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands
Taylor, Nicholas J.,Emer, Enrico,Preshlock, Sean,Schedler, Michael,Tredwell, Matthew,Verhoog, Stefan,Mercier, Joel,Genicot, Christophe,Gouverneur, Véronique
supporting information, p. 8267 - 8276 (2017/06/27)
Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.
Ketanserin Analogues: Structure-Affinity Relationships for 5-HT2 and 5-HT1C Serotonin Receptor Binding
Herndon, Jeff L.,Ismaiel, Abd,Ingher, Stacy P.,Teitler, M.,Glennon, Richard A.
, p. 4903 - 4910 (2007/10/02)
Ketanserin is the prototypic 5-HT2 serotonin antagonist; although it has been an important tool for the study of serotonin pharmacology, it has had relatively little impact on drug design because remarkably little is known about its structure-affinity relationships.Furthermore, ketanserin also binds at 5-HT1C receptors and even less is known about the influence of its structural features on 5-HT1C receptor affinity.The present study reveals that the fluoro and carbonyl groups of the 4-fluorobenzoyl portion of ketanserin make small contributions to 5-HT2 binding and that the intact benzoylpiperidine moiety is an important feature.Ring opening of the piperidine ring reduces affinity.Although the quinazoline-2,4-dione moiety also contributes to binding, it appears to play a smaller role and can be structurally simplified with retention of 5-HT2 affinity.N-(4-Phenylbutyl)-4-(4-fluorobenzoyl)piperidine (39), for example, binds with nearly tha same affinity (Ki=5.3 nM) as ketanserin (Ki=3.5 nM).All of the compounds examined bind at 5-HT1C sites with lower affinity than ketanserin, and some of the simplified analogues bind with nearly 10 times the 5-HT2 versus 5-HT1C selectivity of ketanserin; however, none displays > 120 fold selectivity.Several of the compounds, such as the amide 32 and the urea 33 represent examples of new structural classes of 5-HT2 ligands.
