University of Minnesota

University of California

Washington University

Stanley M Parsons

Simon M Efange

Zhude Tu

Robert H Mach

S Mbua Efange

Hui Liu

Hongjun Jin

David O Harris

Wei Wang

Zonghua Luo

Dawn T Bravo

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

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

Methods, compositions and articles of manufacture for assaying a sample for a GHB source are provided. A sample suspected of containing a GHB source is contacted with a first oxidoreductase selective for GHB and an oxidized cofactor. In the presence of GHB in the sample, the first oxidoreductase oxidizes GHB to succinic semialdehyde and reduces the cofactor. The reduced cofactor thus produced can be detected directly, or a hydride abstractor can be used that abstracts a hydride from the reduced cofactor and produces a detectable change. The hydride abstractor can be a second oxidoreductase that oxidizes the reduced cofactor and produces a detectable change in a chromogen or dye. Preferably a visual change is produced, allowing performance of the assay outside of a laboratory setting. Fusion proteins comprising the first oxidoreductase, polynucleotides encoding such proteins, host cells expressing such proteins, and vectors comprising such polynucleotides are also provided. Stabilized formulations of the first oxidoreductase are also provided. Test supports, devices, and compositions and kits comprising reagents for performing such methods are also provided. Techniques for performing the assay in the presence of ethanol and in the presence of GHB precursors in the sample are also provided.

Methods, compositions and apparatuses for detection of gamma-hydroxybutyric acid (GHB)

Compounds of formula I or formula II: ##STR1## wherein R, J, and Q have any of the values defined in the specification, and their pharmaceutically acceptable salts and related radiopharmaceuticals, have anticholinergic activity, and are useful for modulating cholinergic function in mammals. Also disclosed are pharmaceutical compositions, processes for preparing compounds of formula (I) or (II) and intermediates.

Decahydroquinoline-based anti-cholinergic agents

A method for non-invasively mapping cholinergic innervation in a living brain comprises injecting the brain with a radiolabelled vesamicol (hydroxylated phencyclidine (PCP) isomer trans-2-(4-phenyl-piperidino)cyclohexanol) derivatives with anticholinergic properties termed herein 'azavesamicols' in which the cyclohexyl group of vesamicol is replaced with heterocycle of similar size, the piperidyl ring. The radiolabel is then detected externally with a photoscanning device.

Azavesamicols

The compounds are vesamicol (hydroxylated phencyclidine (PCP) isomer trans-2-(4-phenyl-piperidino)cyclohexanol) derivatives with anticholinergic properties termed herein 'azavesamicols' in which the cyclohexyl group of vesamicol is replaced with a heterocycle of similar size, the piperidyl ring. The compounds bind to the vesamicol receptor, a cytoplasmically-oriented site on the cholinergic synaptic vesicle, which is associated with the vesicular transporter of acetylcholine.

Novel anticholinergics which are related to vesamicol are particularly useful when radiolabeled for evaluating cholinergic innervation in the living human brain. The cholinergic deficit in the Alzheimer's brain should be identifiable with these radioligands.

Radiopharmaceutical agents for the detection of Alzheimers disease

The compounds are vesamicol (hydroxylated phencyclidine (PCP) isomer trans-2-(4-phenyl-piperidino)cyclohexanol) derivatives with anticholinergic properties termed herein 'spirovesamicols' which are spirofused piperidines. The compounds bind to the vesamicol receptor, a site on the cholinergic synaptic vesicle, which is associated with the vesicular transporter of acetylcholine.

Spirovesamicols

Radiopharmaceutical agents for the detection of Alzheimer's disease

A compound denominated (2.alpha., 3.beta., 4a.beta., 8a.alpha.)-decahydro-3-(4-phenyl-1-piperidinyl)-2-naphthalenol(DPPN) having the following chemical structure: ##STR1## DPPN is more effective than other known compounds in blocking presynaptic release of acetylcholine at cholinergic synapses.

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Santa Barbara, CA, United States of America

Stanley M Parsons