Enantiomers of 2'-Fluoralky1-6-nitroquipazine as serotonin transporter positron emission tomography imaging agents and antidepressant therapeutics
Inventors
Gerdes, John M. • Bolstad, David B. • Kusche, Brian R.
Assignees
University of Montana Missoula
Publication Number
US-7998962-B2
Publication Date
2011-08-16
Expiration Date
2027-04-26
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Abstract
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′-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.
Core Innovation
The invention provides novel racemic mixtures and individual enantiomers of fluorine-18 or carbon-11 radiolabelled 2'-alkyl-6-nitroquipazine ligands, which function as serotonin transporter (SERT) tracers for positron emission tomography (PET) imaging. These compounds, in both racemic and enantiomerically pure forms, display high pharmacological potency targeting the SERT protein, with strong brain penetration and specific binding in rodent and primate models.
A key problem addressed by the invention is the need for novel, effective PET imaging tracers capable of measuring a range of SERT densities in different cerebral regions. Existing tracers often lack the necessary in vivo properties, such as high SERT affinity, reduced nonspecific binding, and appropriate kinetic profiles for imaging in living brain tissue. The invention solves this by introducing 2'-alkyl-6-nitroquipazine analogs radiolabeled with fluorine-18 or carbon-11 that satisfy these requirements.
These compounds also possess potent antidepressant activity in both in vitro and in vivo assays, exhibiting competitive binding with established antidepressant drugs and significant inhibition of serotonin reuptake. Furthermore, the invention details methods for synthesizing these compounds and provides data supporting their effectiveness as quantitative PET imaging agents for assessing SERT densities in live brains, as well as their therapeutic potential as antidepressants.
Claims Coverage
There are three independent claims covering the compound, the pharmaceutical composition, and the method of treating depression.
2'-fluoralkyl-6-nitroquipazine compounds
A compound having the core structure of 2'-fluoralkyl-6-nitroquipazine, wherein R is selected from the group consisting of CH2OCH3, CH2OH, CH2CH2CH2OCH3, CH2CH2CH2OH, CH2CH2CH2F, and CH2OCH2CH2CH2F. All stereoisomers, both enantiomers and diastereomers, and mixtures thereof, are included.
Pharmaceutical compositions containing 2'-fluoralkyl-6-nitroquipazine
A pharmaceutical composition comprising a compound with the core structure of 2'-fluoralkyl-6-nitroquipazine as defined, formulated for administration.
Method for treating depression using 2'-fluoralkyl-6-nitroquipazine compounds
A method of treating depression comprising administering a therapeutically effective amount of a compound having the structure of 2'-fluoralkyl-6-nitroquipazine, wherein R is as defined above, and including all stereoisomers and mixtures.
The independent claims broadly cover the structural class of 2'-fluoralkyl-6-nitroquipazine derivatives, their use as active ingredients in pharmaceutical compositions, and their application in the treatment of depression.
Stated Advantages
The compounds display superior brain penetration and specific regional cerebral binding, making them effective PET imaging agents for SERT density measurements.
These ligands exhibit high SERT binding affinity and reduced nonspecific binding in vivo.
Radiolabelled forms allow for quantitative, reproducible PET imaging of a range of SERT densities in the living brain.
Non-radioactive forms possess potent antidepressant activity, as demonstrated by competitive SERT binding and inhibition of serotonin uptake.
Documented Applications
Use as SERT tracers in positron emission tomography (PET) imaging to quantify serotonin transporter densities in various brain regions.
Therapeutic application as antidepressant agents, based on their in vitro and in vivo pharmacological SERT binding profiles.
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