Radioactive labeled or non-labeled; use determining drug binding occupancy of a serotonin selective reuptake inhibitor drug; treating depression; 6-nitro-2-(2-substituted piperazino)-quinoline compounds optionally labeled with 18F or 11C

Inventors

Gerdes, John M. • Bolstad, David B. • Kusche, Brian R.

Assignees

University of Montana Missoula

Abstract

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′-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 relates to racemic mixtures and individual enantiomers of fluorine-18 or carbon-11 radio-labelled 2′-alkyl-6-nitroquipazine ligands, which serve as serotonin transporter (SERT) tracers for positron emission tomography (PET) imaging. These novel [11C]2′-alkyloxy- and [18F]2′-fluoroalkyl-6-nitroquipazine radioligands are designed for efficacious imaging of SERT densities across regions of the living primate brain, either as racemic mixtures or enantiomerically pure forms. The compounds have distinct molecular structures and high pharmacological potency for the SERT target protein.

A major problem addressed is the lack of SERT PET imaging agents that can provide reproducible and accurate measurements of a wide range of SERT densities within cerebral regions in the living brain. Previous tracers often failed due to insufficient target-to-reference tissue ratios, poor target protein specificity, or inadequate in vivo profiles. The invention solves this problem by providing new radiolabeled compounds with high SERT binding affinity, limited nonspecific binding, and suitable in vivo kinetic profiles, thus enabling robust PET imaging of SERT.

The invention also covers the non-radioactive ligand forms, which demonstrate therapeutic antidepressant potential based on their in vitro and in vivo SERT binding properties in rodent brain and cells expressing human serotonin transporter (hSERT). The compounds described, specifically the 2′-alkyl-6-nitroquipazine analogs with radiolabeled groups at suitable side chain positions, allow both for PET quantification of SERT in various brain regions and potential therapeutic use as antidepressant agents.

Claims Coverage

There are two independent claims, one directed to the compound and one to a method of determining drug binding occupancy at the serotonin transporter.

The independent claims cover both the novel class of radiolabeled or non-radiolabeled 6-nitroquinoline-piperazine compounds, defined by their substitution patterns, and the use of these compounds for determining serotonin transporter binding occupancy of selective reuptake inhibitor drugs.

Stated Advantages

Documented Applications