General Electric Company

Other

Eli Lilly and Company

Sean Richard Dinn

Bruce Fletcher Johnson

Michael James Rishel

Kande Kankanamalage Dayarathna Amarasinghe

Anup Sood

Robert Jason Herr

Nathan Bryan Mantlo

Xinchao Chen

Todd Fields

Kande Kankananamalage Dayarathna Amarasinghe

Thomas Pirrie Treynor

Saravanan Parthasarathy

Christopher Lawrence Cioffi

Ana Isabel Mateo-Herranz

The present invention provides novel alpha-fluoroalkyl dihydrotetrabenazine compounds I wherein Ris a C-Cfluorinated aliphatic radical; Ris hydrogen or a C-Caliphatic radical; Ris hydrogen or a C-Caliphatic radical; and Ris a C-Caliphatic radical, a C-Ccycloaliphatic radical, or a C-Caromatic radical. The alpha-fluoroalkyl dihydrotetrabenazine compounds are provided in both racemic and enantiomerically enriched forms and may comprise either or both of fluorine-18 and fluorine 19. The alpha-fluoroalkyl dihydrotetrabenazine compounds are believed to possess high affinity for VMAT-2, a biomarker implicated in human diabetes. The alpha-fluoroalkyl dihydrotetrabenazine compounds comprising a fluorine-18 group are useful as PET imaging agents targeting the VMAT-2 biomarker. The non-radiolabled alpha-fluoroalkyl dihydrotetrabenazine compounds are useful as probes for the discovery of PET imaging agents.

Alpha-fluoroalkyl dihydrotetrabenazine imaging agents and probes

Methods of activating an apo-peroxidase are provided. The methods include the steps of providing a solution comprising an apo-peroxidase and a heme choline ester, hydrolyzing the heme choline ester with a choline esterase, and converting the apo-peroxidase to active peroxidase. The methods disclosed herein also provide for detecting the presence of an analyte in a sample. The methods include providing a binder capable of specifically binding the analyte wherein the binder is attached to a solid surface, applying the sample to the solid surface under conditions that permit binder-analyte binding, adding a choline esterase-conjugated binder that binds to the analyte, adding an apo-peroxidase, a heme choline ester, a peroxide, and a peroxide-activated signal generator, and detecting the signal produced by the peroxide-activated signal generator. An associated kit and components are also provided.

Heme choline esters and uses thereof

The present invention provides novel fluoroalkyl tetrabenazine carbinol compounds having structure I wherein Ris a C-Cfluorinated aliphatic radical; Ris a C-Caliphatic radical; Ris hydrogen or a C-Caliphatic radical; Ris hydrogen or a C-Caliphatic radical; and Ris hydrogen, a C-Caliphatic radical, a C-Ccycloaliphatic radical, or a C-Caromatic radical. In a particular embodiment, &#x2014;ORis an ester moiety. The fluoroalkyl tetrabenazine carbinol compounds are provided in both racemic and enantiomerically enriched forms and may comprise either or both of fluorine-18 and fluorine 19. The fluoroalkyl tetrabenazine carbinol compounds are shown to possess high affinity for VMAT-2, a biomarker implicated in human diabetes. The fluoroalkyl tetrabenazine carbinol compounds comprising a fluorine-18 group are useful as PET imaging agents targeting the VMAT-2 biomarker. The non-radiolabled fluoroalkyl tetrabenazine carbinol compounds are useful as probes for the discovery of PET imaging agents.

Fluoroalkyl tetrabenazine carbinol compounds as imaging agents and probes

A method of preparing a tetrabenazine compound (TBZ compound) having structure I comprising the steps of reacting a nucleophilic alkenyl species with aldehyde compound II and oxidizing the resultant allylic alcohol to provide enone III. The protecting group Pon the tetrahydroisoquinoline nitrogen is removed and the resultant deprotected intermediate is induced to undergo an amino cyclization reaction to provide a product TBZ compound having structure I. The method may be used to prepare either enantiomeric form of tetrabenazine; (+)-tetrabenazine or (&#x2212;)-tetrabenazine. Alternatively the method may be adapted to provide a mixture enriched in one tetrabenazine enantiomer, a racemic mixture, or a diastereomeric mixture of tetrabenazine compounds. In addition, the present invention provides novel synthetic intermediate compositions which may be used to prepare either or both enantiomers of tetrabenazine, derivatives of tetrabenazine, and analogs of tetrabenazine.

Intermediates useful for making tetrabenazine compounds

The present invention provides novel fluorophilic compounds having structure VII wherein Ris a C-Caliphatic, a C-Ccycloaliphatic, or a C-Caromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent; Ris a C-Caliphatic radical; Ris hydrogen or a C-Caliphatic radical; Ris hydrogen or a C-Caliphatic radical; and Ris hydrogen, a C-Caliphatic radical, a C-Ccycloaliphatic radical, or a C-Caromatic radical. The fluorophilic compounds are provided in both racemic and enantiomerically enriched forms and are useful as intermediates in the preparation of novel PET imaging agents and probes useful in the discovery and performance assessment of PET imaging agents. The fluorophilic compounds are particularly useful in the preparation of PET imaging agents and probes having a high affinity for VMAT-2, a biomarker implicated in human diabetes and other illnesses such as Parkinson's disease.

Intermediates for fluorinated tetrabenazine carbinol compounds imaging agents and probes

The present invention provides novel fluorophilic compounds having structure VII wherein Q is a carbonyl group, a protected carbonyl group, a hydroxy methine group, or a protected hydroxy methine group; Ris a C-Caliphatic, C-Ccycloaliphatic, or C-Caromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent; Ris hydrogen or a C-Caliphatic radical; and Ris hydrogen or a C-Caliphatic radical. The fluorophilic compounds are provided in both racemic and enantiomerically enriched forms and are useful as intermediates in the preparation of novel PET imaging agents and probes useful in the discovery and performance assessment of PET imaging agents. The fluorophilic compounds are particularly useful in the preparation of PET imaging agents and probes having a high affinity for VMAT-2, a biomarker implicated in human diabetes and other illnesses such as Parkinson's disease.

Intermediates for alpha-fluoroalkyl tetrabenazine and dihydrotetrabenazine imaging agents and probes

The present invention provides novel alpha-fluoroalkyl compounds having structure I and the corresponding dihydrotetrabenazine compounds IV wherein Ris a C-Cfluorinated aliphatic radical; Ris hydrogen or a C-Caliphatic radical; and Ris hydrogen or a C-Caliphatic radical. The alpha-fluoroalkyl compounds are provided in both racemic and enantiomerically enriched forms and may comprise either or both of fluorine-18 and fluorine 19. The alpha-fluoroalkyl compounds are shown to possess high affinity for VMAT-2, a biomarker implicated in human diabetes. The alpha-fluoroalkyl compounds comprising a fluorine-18 group are useful as PET imaging agents targeting the VMAT-2 biomarker. The non-radiolabled alpha-fluoroalkyl compounds are useful as probes for the discovery of PET imaging agents.

Alpha-fluoroalkyl tetrabenazine and dihydrotetrabenazine imaging agents and probes

The present invention provides novel fluorinated ether compounds having structure I wherein Ris a C-Cfluorinated aliphatic radical; Ris a C-Caliphatic radical, or a C-Ccycloaliphatic radical; Ris hydrogen or a C-Caliphatic radical; and Ris hydrogen or a C-Caliphatic radical. The fluorinated ether compounds are provided in both racemic and enantiomerically enriched forms and may comprise either or both of fluorine-18 and fluorine 19. The fluorinated ether compounds are shown to possess high affinity for VMAT-2, a biomarker implicated in human diabetes. The fluorinated ether compounds comprising a fluorine-18 group are useful as PET imaging agents targeting the VMAT-2 biomarker. The non-radiolabeled fluorinated ether compounds are useful as probes for the discovery of PET imaging agents.

Fluorinated dihydrotetrabenazine ether imaging agents and probes

The present invention provides novel fluorophilic compounds having structure VI wherein Ris a C-Caliphatic, a C-Ccycloaliphatic, or a C-Caromatic radical comprising at least one functional group susceptible to reaction with nucleophilic fluoride ion or an electrophilic fluorinating agent; Ris a C-Caliphatic radical, or a C-Ccycloaliphatic radical; Ris hydrogen or a C-Caliphatic radical; and Ris hydrogen or a C-Caliphatic radical. The fluorophilic compounds are provided in both racemic and enantiomerically enriched forms and are useful as intermediates in the preparation of novel PET imaging agents and probes useful in the discovery and performance assessment of PET imaging agents. The fluorophilic compounds are particularly useful in the preparation of PET imaging agents and probes having a high affinity for VMAT-2, a biomarker implicated in human diabetes and other illnesses such as Parkinson's disease.

Growing community of inventors

Delmar, NY, United States of America

Sean Richard Dinn