Serotonin 5-HT1A receptors are implicated in Alzheimers disease, dementia, anxiety, schizophrenia, and depression, and significant efforts have been undertaken to develop various compounds that bind to these receptors for potential use in diagnosis and therapy of disorders associated with serotonin 5-HT1A receptors. Among other proposed approaches, particularly desirable compounds include those suitable for selective positron emission tomography (PET) analysis. While currently known compounds target the serotonin 5-HT1A receptors to at least some degree, numerous difficulties nevertheless exist. Among other problems, all or almost all of the known compounds are metabolized at a relatively fast rate, and/or are eliminated from plasma is an undesirably short time. Thus, data analysis is often difficult. Still further, the synthesis of such compounds is frequently difficult to achieve in adequate yields. Moreover, where 18F is used as a radiolabel, compounds are often rendered chemically instable. Worse yet, affinity of 18F-labeled compounds to the target receptor is typically relatively low. Thus, while numerous compositions and methods for serotonin 5-HT1A receptor ligands are known in the art, all or almost all of them suffer from one or more disadvantages. Therefore, there is still a need to provide improved compositions and methods for such ligands, especially for 18F-labeled ligands.
University of California researchers have developed compositions and methods for targeting the serotonin 5-HT1A receptor, wherein the compounds in such compositions selectively bind to the serotonin 5-HT1A receptor and (in most instances) evoke an antagonistic effect. Preferably, where the compound is labeled using a PET detectable radio ligand (e.g., 11C or 18F), it is contemplated that binding to and/or location of the serotonin 5-HT1A receptor may be analyzed in vitro and in vivo. Moreover, such compounds may also be employed to determine the serotonin concentration in in vitro and in vivo (e.g., using competitive displacement analysis).
The compounds are useful for diagnosis and/or treatment of various diseases involved with the serotonin 5-HT1A receptor, as well as for research and drug development and drug-receptor interactions. The structure of the compound allows it to (a) bind to the serotonin 5-HT1A receptor, (b) have an antagonistic effect, and (c) is detectable in vitro and in vivo using known detection methods. Detection of the compound in vivo and/or in vitro collocates with the location of the serotonin 5-HT1A receptor. These compounds may also be active and/or prepared as a metabolites, as prodrugs, and/or otherwise modified compound, where the modified compound exhibits less pharmacological activity (as compared to the unmodified compound) and the modified compound is converted within a target cell or target organ back into the unmodified form. For example, conversion of compounds into prodrugs may be useful where the active drug is too toxic for safe systemic administration, or where the compound is poorly absorbed by the digestive tract, or where the body breaks down the compound before reaching its target. The compounds may also be transformed by the hepatic phase I and/or phase II enzyme system, or by gastric acidity, intestinal microbial environment, or other biochemical process. Thus, suitable compounds may be oxidized, hydroxylated, ligated to a carbohydrate, etc. Based on the observed and expected stability of the compounds, they may be useful for determining the levels of endogenous serotonin and determining the location, function, and/or quantity of receptors in neural (and other) tissue. The compounds and compositions are suitable for diagnostic and/or therapeutic purposes.
|United States Of America||Issued Patent||RE,46,688||09/25/2012||2005-540|
|United States Of America||Issued Patent||7,731,940||06/08/2010||2005-540|