Washington University

University of California

Zhude Tu

Robert H Mach

Michael John Welch

Paul T Kotzbauer

William G Hawkins

Stanley M Parsons

Richard S Hotchkiss

Douglas J Rowland

Hui Liu

Xuyi Yue

Rebecca Aft

Wenhua Chu

Suwanna Vangveravong

Junfeng Li

Hongjun Jin

Douglas J Rowland, Jr

Hao Jiang

Buck Rogers

Junbin Han

Vijai Kumar Reddy Tangadanchu

Dhruva D Dhavale

Wei Wang

Adam Rosenberg

Zonghua Luo

Among the various aspects of the present disclosure is the provision of SphK inhibitors and methods of making and using same. An aspect of the present disclosure provides for an SphK2 inhibiting agent, wherein the SphK2 inhibiting agent is a 1,2,3-triazole having SphK2 inhibiting activity and SphK2 selectivity.

SphK inhibitors and methods of making and using same

The present invention generally relates to various compounds that are useful as α-synuclein ligands. The invention further relates to methods of using these compounds and their radiolabeled analogs for the detection of synucleinopathies, including Parkinson's disease (PD).

Alpha-synuclein ligands

Among the various aspects of the present disclosure is the provision of a compositions for binding sphingosine-1-phosphate receptor 1 (S1P1), imaging of S1P1, and methods of use thereof. Provided are imaging agents for imaging S1P1 and S1P1 associated diseases, disorders, and conditions. Also provided are therapeutic compositions and methods for the treatment of S1P1 associated diseases, disorders, and conditions.

Compositions for binding sphingosine-1-phosphate receptor 1 (S1P1), imaging of S1P1, and methods of use thereof

The present invention generally relates to various compounds that are useful as vesicular acetylcholine transporter (VAChT) ligands. The invention further relates to methods of using these compounds and their radiolabeled analogs for the detection of neurodegenerative diseases including Parkinson's disease (PD), and Alzheimer's disease (AD).

Sulfur-containing compounds targeting vesicular acetylcholine transporter

The present invention generally relates to various compounds that are useful as &#x3b1;-synuclein ligands. The invention further relates to methods of using these compounds and their radiolabeled analogs for the detection of synucleinopathies, including Parkinson's disease (PD).

Bipiperidinyl compounds and salts thereof are disclosed. The compounds include high affinity ligands for &#x3c3;receptors. Some compounds are also highly selective for &#x3c3;receptor compared to &#x3c3;receptor. Compounds can comprise radioisotopes, includingF orC. Radiolabeled compounds can be used as probes for imaging distribution of &#x3c3;receptor in a subject such as a human using positron emission tomography (PET) scanning.

Compounds comprising 4-benzoylpiperidine as a sigma-1-selective ligand

Pegylated fluoroalkoxybenzamide compounds which selectively bind Sigma-2 receptors are disclosed. These compounds, when labeled with a positron-emitting radioisotope such asF, can be used as radiotracers for medical imaging such as imaging of tumors by positron emission tomography (PET). In addition, these compounds, when labeled withI, can be used as radiotracers for imaging of tumors by single photon emission computed tomography (SPECT). Methods for synthesis of these compounds are also disclosed.

Pegylated fluorobenzamide analogues, their synthesis and use in diagnostic imaging

Fluoroalkoxybenzamide compounds which selectively bind Sigma-2 receptors are disclosed. These compounds, when labelled withF, can be used as radiotracers for imaging of tumors by positron emission tomography (PET). In addition, these compounds, when labelled withI, can be used as radiotracers for imaging of tumors by single photon emission computed tomography (SPECT). Methods for synthesis of these compounds are also disclosed.

Radiolabelled fluorobenzamide analogues, their synthesis and use in diagnostic imaging

A series of N-substituted 9-azabicyclo[3.3.1]nonan-3&#x3b1;-yl phenylcarbamate analogs are disclosed, as well as methods of their preparation. Their affinities for sigma (&#x3c3;1 and &#x3c3;2) receptors are described. Two new compounds, N-(9-(4-aminobutyl)-9-azabicyclo[3.3.1]nonan-3&#x3b1;-yl)-N'-(2-methoxy-5-methylphenyl)carbamate and N-(9-(6-aminohexyl)-9-azabicyclo[3.3.1]nonan-3&#x3b1;-yl)-N&#x2032;-(2-methoxy-5-methylphenyl)carbamate, are shown to have a high affinity and selectivity for &#x3c3;2 versus &#x3c3;1 receptors. Among the disclosed compounds are biotinylated and fluorescent analogs. These compounds can serve as probes to the &#x3c3;2 receptor. In addition, some disclosed compounds can induce apoptotic cell death by both caspase-dependent and caspase-independent mechanisms, and are effective for treatment of tumors. The compounds can be used as chemotherapeutics or chemosensitizers in the treatment of a wide variety of solid tumors.

Therapeutic uses of bicyclic ligands of sigma 2 receptor

Radiolabelled benzamide analogues, their synthesis and use in diagnostic imaging

Methods for detection of cancer cells and for determining the proliferative status of cells in a tissue sample in vitro are disclosed. These methods comprise contacting a tissue sample with a radiolabeled compound or salt thereof of Formula wherein at least one of X, Y, and Z comprises a radioisotope, n is an integer from 2 to about 10; and each of A and Ais a C-Calkoxyl, a C-Cfluoroalkyl or a C-Cfluoroalkoxyl. The methods further comprise detecting the distribution of the radioisotope in the tissue sample, whereby a cell having a high density of the radioisotope compared to quiescent cells is diagnostic for a cancer cell.

Detection of cancer cells in vitro using sigma-2 receptor ligands as radiotracers

Sigma 2 receptor ligands and therapeutic uses therefor

Novel benzamide compounds of Formula (I), Formula (II), and Formula (III), salts, water soluble salts, analogs and radiolabeled counterparts thereof as sigma-2 receptor radiotracers for imaging the proliferative status of solid tumors. A method for diagnosing a mammal for the presence of a mammalian tumor therein comprises administering to the mammal a diagnostic imaging detectable effective amount of a benzamide compound having a structure illustrated in Formula (I), Formula (II) and Formula (III) and detecting binding of the compound to a tumor in the mammal. A method for diagnostic imaging of a mammalian tissue having cell surface sigma-2 receptors comprising administering to a mammal a diagnostic imaging amount of a compound having a structure illustrated in Formula (I) Formula (II) and Formula (III) and detecting an image of a tissue having an ample cells with sigma-2 receptors.

Sigma-2 receptor radiotracers for imaging the proliferative status of solid tumors

Novel benzamide compounds of Formula (I), Formula (II) and Formula (III, salts, water soluble salts, analogs and radiolabeled counterparts thereof as sigma-2 receptor radiotracers for imaging the proliferative status of solid tumors. A method for diagnosing a mammal for the presence of a mammalian tumor therein comprises administering to the mammal a diagnostic imaging detectable effective amount of a benzamide compound having a structure illustrated in Formula (I), Formula (II) and Formula (III) and detecting binding of the compound to a tumor in the mammal. A method for diagnostic imaging of a mammalian tissue having cell surface sigma-2 receptors comprising administering to a mammal a diagnostic imaging amount of a compound having a structure illustrated in Formula (I) Formula (II) and Formula (III) and detecting an image of a tissue having an ample cells with sigma-2 receptors.

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Frontenac, MO, United States of America

Zhude Tu