Design and Synthesis of Fluoroalkylpyridyl Ethers as Potential Pet Radioligands for A4B2 Nicotinic Acetylcholine / Labeled A4B2 Ligands and Methods Therefor

Tech ID: 25214 / UC Case 2003-432-3

Brief Description

Researchers have developed compounds to bind to α4β2 nicotinic acetylcholine receptors to evoke antagonistic effects both in vitro and in vivo environments.

Full Description

α4β2 receptors, a class of nicotinic acetylcholine receptor (nAChR), are thought to play a role in various diseases such as brain disorders (Alzheimer’s disease), behavioral diseases ((schizophrenia or substance abuse), neoplasms (lung cancer), amongst others. It is of interest to study the α4β2 receptor system. Methods to do so involve radiolabeling compounds that bind to the α4β2 receptors for posititron emission tomography (PET) and single photon emission computed tomorgraphy (SPECT) imaging. These compounds suffer from drawbacks such as having toxicity issues and undesirable kinetic properties.

Researchers at UC Irvine have developed a compounds and its compositions that overcome the disadvantages associated with existing radioligands for binding of the α4β2 receptors. The developed compounds, shown in Figure 1, has antagonistic effects when binding to the α4β2 receptors, and have demonstrated these effects both in vitro and in vivo.

Figure 1
Figure 1.

The invented compounds, which have demonstrated high specificity to α4β2 receptors, are useful for both diagnosis and/or treatment of various diseases (Alzheimer’s disease, schizophrenia, oncology, and substance abuse). Various analogs of the compound can be synthesized with modifications to the basic compound structure. The compound can be administered using various routes, including orally, parenterally, by inhalation, topically, rectally, nasally, or via an implanted reservoir.

Figure 8 

Figure 8 is a horizontal brain slice showing the binding of the 18F-nifene (an analog of the invented compound) to α4β2 receptors to the thalamus, presubiculum, and cortex (left). Binding reflects the concentration of the receptors. Addition of nicotine cause reversal of the 18F-nifene binding.

Table 1 

Table 1 shows in vivo binding in various regions of the rat brain. Levels in the blood decreased from 0.25% ID/g at 2 min to <0.03% ID/g at 120 min. Binding in the thalamus was highest (>0.3% ID/g) at 60 min, after which time it exhibited significant clearance. The thalamus-to-cerebellum ratio was about 3 at 60 min. Binding in the Ctx was greater than that in the cerebellum. Ratios of the thalamus to the cerebellum decreased at 120 min, indicative of clearance of the radiotracer from receptor sites. Blocking studies were performed by subcutaneous injection of nicotine tartarate (10 mg/kg), which decreased binding in the thalamus (Table 1). These results suggest that 18F-nifrolidine is stable in vivo in rodents, is able to cross the blood-brain barrier, and is able to bind preferentially to α4β2 receptor-rich regions, and the binding to receptor sites is reversible. Rats were preinjected subcutaneously with nicotine ditartarate (10 mg/kg) 5 min before injection of 3.7 MBq of 18F-nifrolidine. NT=not tested. Groups of male Sprague-Dawley rats (n=3) were injected intravenously with 3.7 MBq of 18F-nifrolidine and sacrificed at different times.

Suggested uses

This technology has applications in diagnostic and therapeutic applications with disorders involving α4β2 receptors, such as Alzheimer’s disease, schizophrenia, oncology, and substance abuse. Radiolabelling of these compounds can yield compounds suitable for PET and SPECT imaging. This invention can also be used as a research tool to create additional labels for α4β2 receptors.


This technology will provide significant advantages, including (1) The ligands are antagonists and therefore have lower toxicity, (2) the compounds can be easily radiolabeled with fluorine-18 or iodine-123, (3) the compounds have high selectivity for α4β2 receptors in the brain, (4) the radiolabeled compounds are highly stable in vivo, and (5) the radiolabeled compounds are suitable for PET and SPECT imaging.Furthermore, the compound can read out through other methods such as through autoradiography or scintigraphy by merely changing the label.

Patent Status

Country Type Number Dated Case
United States Of America Issued Patent 9,029,557 05/12/2015 2003-432


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