University of Montana

University of Connecticut

David B Bolstad

John M Gerdes

Brian R Kusche

Dennis L Wright

Michael R Braden

Amy C Anderson

Phillip M Pelphrey

Tammy M Joska

Erin S D Bolstad

Veljko Popov

August W Barany

The compositions and methods described herein discloses the design, synthesis and testing of compounds that act as inhibitors of DHFR. The basic scaffold of these inhibitors includes a 2,4-diaminopyrimidine ring with a propargyl linker to another substituted aryl, bicyclo or heteroaryl ring. These DHFR inhibitors are potent and selective for many different pathogenic organisms, including the DHFR enzyme from bacteria such asand methicillin-resistant, fungi such asandand protozoa such asand. These compounds and other similar compounds are also potent against the mammalian enzyme and may be useful as anti-cancer therapeutics.

Inhibitors of dihydrofolate reductase with antibacterial antiprotozoal, antifungal and anticancer properties

Racemic mixtures and individual enantiomers of fluorine-18 or carbon-11 radiolabelled 2'-alkyl-6-nitroquipazine ligands are serotonin transporter (SERT) tracers for positron emission tomography (PET) imaging. The non-radioactive ligand forms possess therapeutic antidepressant in vitro and in vivo pharmacological binding profiles in rodent brain and cells expressing human serotonin transporter (hSERT). Twelve 2&#x2032;-alkyl-6-nitroquipazine ligands potently bind in sub-nanomolar concentrations to the pre-synaptic SERT binding site where established antidepressant drugs bind and inhibit the re-uptake of the neurotransmitter serotonin (5-HT). In vivo tracer studies in rats as well as monkey PET scan trial have demonstrated the fluorine-18 and carbon-11 positron radionuclide labeled tracers perform as quantitative tracers of specific binding the SERT protein in live brain.

Enantiomers of 2'-Fluoralky1-6-nitroquipazine as serotonin transporter positron emission tomography imaging agents and antidepressant therapeutics

Racemic mixtures and enantiomerically pure forms of novel 1-[(2'-substituted)-piperazin-1&#x2032;-yl]-isoquinolines are norepinephrine (NE) transporter (NET) inhibitor compounds. Compounds of the invention are considered therapeutic agents for central nervous system (CNS) diseases and disorders, without limitation, including neurodegeneration, anxiety, depression, attention deficit disorders, drug dependency, and post traumatic stress disorder. Examples of the chemical syntheses of the compounds of the invention are provided. The isoquinoline compounds of the invention competitively bind at NET at nanomolar concentrations. The isoquinoline agents of the invention bind selectively to NET over other competitive transporter targets and receptor binding sites, including those of serotonin and dopamine, amongst others. The chemical syntheses of the invention are suitable for labeling with radionuclide atoms. Radiolabeled forms of the novel 1-[(2&#x2032;-substituted)-piperazin-1&#x2032;-yl]-isoquinoline compounds are positron emission tomography and single photon emission tomography imaging tracers. Methods of in vivo imaging with the tracers within various subjects and tissues therein, including regions of the brain, are provided. Imaging methods with the tracers in combination other NET inhibitor agents are provided. The imaging methods within subjects allow quantitative detection of NET, determinations of NET distributions, and measures of tracer interactions at NET in the presence or absence of non-radioactive NET agents. The tracer imaging methods are suitable to locate, diagnose, identify, evaluate, detect or quantitate NET, or abnormalities of NET, or NE abnormalities; that are associated with various CNS diseases and disorders.

1-[(2'-substituted)-piperazin-1&#x2032; -yl]-isoquinolines as norepinephrine transporter inhibitor therapeutics and positron emission tomography imaging agents

Racemic mixtures and individual enantiomers of fluorine-18 or carbon-11 radio-labelled 2'-alkyl-6-nitroquipazine ligands are serotonin transporter (SERT) tracers for positron emission tomography (PET) imaging. The non-radioactive ligand forms possess therapeutic antidepressant in vitro and in vivo pharmacological binding profiles in rodent brain and cells expressing human serotonin transporter (hSERT). Twelve 2&#x2032;-alkyl-6-nitroquipazine ligands potently bind in sub-nanomolar concentrations to the pre-synaptic SERT binding site where established antidepressant drugs bind and inhibit the re-uptake of the neurotransmitter serotonin (5-HT). In vivo tracer studies in rats as well as monkey PET scan trial have demonstrated the fluorine-18 and carbon-11 positron radionuclide labeled tracers perform as quantitative tracers of specific binding the SERT protein in live brain.

Enantiomers of 2'-fluoralkyl-6-nitroquipazine as serotonin transporter positron emission tomography imaging agents and antidepressant therapeutics

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Vernon, CT, United States of America

David B Bolstad