Design and Synthesis of PET Radioligands for alpha 4 beta 2 Nicotinic Acetylcholine Receptors

Tech ID: 18860 / UC Case 2003-432-0

Background

Nicotinic acetylcholine receptors (nAChRs) belong to the superfamily of ligand-gated ion channels and are distributed widely in the human and nonhuman brain. Several nAChRs have been identified and characterized pharmacologically and have distinct patterns of distribution in the brain. The nicotine alpha 4 beta 2 receptor subtypes are thought to play a role in various diseases, including various brain disorders (e.g., Alzheimer's disease), behavioral disorders (e.g., schizophrenia or substance abuse), various neoplasms (e.g., lung cancer), and other diseases, and may also be involved in the addiction to nicotine in chronic tobacco users (tobacco use may increase the number of the alpha 4 beta 2 receptor sites). The development of noninvasive imaging methods using PET and SPECT of the alpha 4 beta 2 receptor system has gained significant interest. Therefore, and not surprisingly, the development of noninvasive imaging methods using PET and SPECT of the alpha 4 beta 2 receptor system has gained significant interest. However, current radiotracers suffer from several drawbacks, including rapid clearance, toxicity, and undesirable kinetic parameters. Consequently, there is still a need to provide improved compositions and methods for radioligands for receptors of the alpha 4 beta 2 receptor type.

Technology Description

The present invention is directed to compositions and methods for targeting the alpha 4 beta 2 receptor, wherein compounds in such compositions will selectively bind to the alpha 4 beta 2 receptor. Where the compounds are labeled, it is contemplated that binding and/or location of the alpha 4 beta 2 receptor may be analyzed in vitro and in vivo using PET and SPECT analysis. Alternatively, and/or additionally contemplated compounds can be used as antagonists, partial agonists or agonists in the treatment of diseases or conditions associated with alpha 4 beta 2 dysfunction.

Applications

Contemplated compounds may be particularly useful as ligands for the alpha 4 beta 2 nAChR, and most preferably as an antagonist for the alpha 4 beta 2 nAChR. Numerous diagnostic, therapeutic, and academic uses are contemplated due to the specific binding of the compounds presented herein (Km to alpha 4 beta 2 nAChR is typically at least 10-100 times less than compared to other receptors or biological structures).

Where contemplated compounds are radiolabeled, such compounds may be useful for location and/or quantification of alph 4 beta2 nAChR in a biological tissue. Suitable diagnostic methods will generally depend on the particular label. The compound can be detected in vivo via PET or SPECT analysis or in vitro via autoradiography or scintigraphy.

Location and quantification of the alpha 4 beta 2 receptor in vivo may be particularly useful in diagnostic use, while quantification of the receptor and/or binding of contemplated labeled compounds in vitro may be especially useful in characterization of a mutant form of a receptor, or in competitive analysis with a second ligand. Therefore, labeled compounds may also be particularly useful in the development and/or characterization of new ligands.

In other examples of contemplated uses, and particularly where compounds presented herein are not radioisotope-containing compounds, it should be recognized that the binding of the compounds to the alpha 4 beta 2 nAChR as antagonist (or in some cases as agonist) may be used in a therapeutic manner for treatment of diseases or conditions that are associated with the alpha 4 beta 2 nAChR. For example, diseases and conditions to be treated with contemplated compounds include cognitive dysfunctions and/or attentional disorders (e.g., anxiety disorders, lack of mental focus, ADHD), neurodegenerative diseases (e.g., Alzheimer's and Parkinson's), schizophrenia, pain, depression, epilepsy, Tourette's syndrome, small-cell lung carcinoma, and tobacco dependence.

Patent Status

Country Type Number Dated Case
United States Of America Issued Patent 9,029,557 05/12/2015 2003-432
United States Of America Issued Patent 8,378,109 02/19/2013 2003-432
 

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