News Column

Patent Issued for Butyrylcholinesterase Ligands as Diagnostic Tools and Treatment for Diseases of the Nervous System

August 19, 2014



By a News Reporter-Staff News Editor at Life Science Weekly -- According to news reporting originating from Alexandria, Virginia, by NewsRx journalists, a patent by the inventors Darvesh, Sultan (Halifax, CA); Joy, Eric (Lower Sackville, CA); Martin, Earl (Halifax, CA); Macdonald, Ian (Dartmouth, CA); Pottie, Ian (Middle Sackville, CA), filed on August 28, 2009, was published online on August 5, 2014 (see also Treventis Corporation).

The assignee for this patent, patent number 8795630, is Treventis Corporation (Bernville, PA).

Reporters obtained the following quote from the background information supplied by the inventors: "Alzheimer's disease (AD) is a common neurodegenerative disorder causing dementia and a major cause of death. In AD there are three major microscopic features that are recognized as the hallmarks of the disease, namely, neuritic plaques (NP), neurofibrillary tangles (NFT) and amyloid angiopathy (AA). In addition, there is widespread cell loss, particularly of cholinergic neurons in the brain. Loss of cholinergic cells leads to reductions in the levels of the neurotransmitter acetylcholine (ACh), its synthesizing enzyme choline acetyltransferase, as well as its deactivating enzyme actetylcholinersterase (AChE). Reduction of cholinergic neurotransmission leads to some of the symptoms of AD. Because of this reduced cholinergic activity, drugs such as donepezil, metrifonate, rivastigmine, huperzine A, and tetrahydroaminoacridine, which inhibit the activity of cholinesterase and increase the level of ACh, have been used to treat the symptoms (though not the disease progression) of AD.

"Determining when to begin therapy for AD is an extremely difficult task, however, because confirmation of the diagnosis of dementias such as AD is difficult at present and can only be truly confirmed by autopsy. Distinguishing between different forms of dementia such as AD, dementia with Lewy bodies, vascular dementia and frontotemporal dementia is challenging. Furthermore, early diagnosis of incipient dementia, such as mild cognitive impairment, becomes imperative for beginning symptomatic therapy, as well as when new disease-modifying AD drugs are developed. Thus, there remains a great need for a means of identifying and diagnosing AD at an early stage.

"Neuroimaging is increasingly used to assist in diagnosis, but no satisfactory diagnostic tool has heretofore emerged. Structural imaging such as Computer Assisted Tomography (CAT) and Magnetic Resonance Imaging (MRI) provide information about changes in the brain, such as atrophy, stroke, malignancy and white matter changes, but at a gross anatomical level. Functional imaging using Single Photon Emission Computer Tomography (SPECT) and Positron Emission Tomography (PET) are non-specific. For example, one of the PET ligands used is .sup.18-fluorodeoxyglucose and, for SPECT, .sup.99mTc hexa-methyl-propyl-amino oxime (HMPAO) or .sup.99mTc ethylene dicysteine di-ethyl ester (ECD). Each of these techniques provides information regarding reduced functional integrity of different parts of the brain, but do not provide information as to why there is reduced function in these regions. More recently, radioligands that bind to the AD-implicated .beta.-amyloid protein have been developed (for example, AV-45). These ligands provide information as to whether, and where, .beta.-amyloid is present in the brain. From a neuropathologic perspective, deposition of amyloid and formation of NP is one of the central mechanisms in the evolution of AD. However, amyloid plaques are also found in brains of elderly individuals who do not have dementia, which limits the applicability of this approach.

"A technique of greater utility involves binding to cholinesterases, especially butyrylcholinesterase (BuChE). Although the level of AChE is reduced in AD, the level of the closely related enzyme BuChE is increased in AD brains. There is a severe loss of basal forebrain cholinergic neurons in AD (Coyle J. T., Price D. L., and DeLong M. R., 1983, Science 219:1184-90), and there is a marked decrease in the levels of AChE and a similarly marked increase in the levels of BuChE (Perry E. K., Perry R. H., Blessed G., and Tomlinson B. E., 1978, Neuropath. Appl. Neurobiol. 4:273-277; Mesulam M-M. and Geula C., 1994, Ann. Neurol. 36:722-727). BuChE is found in all the neuropathological lesions associated with AD (NP, NFT and AA). Amyloid plaques in individuals without dementia are 'benign' and they become 'malignant', causing dementia, when they are transformed into NP. Importantly, BuChE is found in NP in brains of patients with AD rather than plaques found in brains of elderly individuals without AD. Taken together, these observations show that in brains of patients with AD there is a significant alteration of the biochemical properties of BuChE that alters its normal regulatory role in the brain (Guillozet A. L., Smiley J. F., Mash D. C., and Mesulam M-M., 1997, Ann. Neurol. 42:909-918). As such, high affinity labeling of BuChE, particularly with radioligands, has utility in the early diagnosis of AD.

"Within the context of detecting BuChE in the brain, only one experimental radioligand is available, namely, 1-[.sup.11C]-methyl-4-piperidinyl n-butyrate. However, this compound has disadvantages. First, it is labeled with .sup.11C, emitting positrons that can only be detected by PET scanners, which are not as widely available as SPECT scanners. Second, the radioactive label is attached to the molecule in the portion that is an initial leaving group in the mechanism of the enzyme catalyzed hydrolysis of this radiopharmaceutical. Thus, the radioactive atom intended to label the enzyme is lost in the early stages of the reaction, which would lead to short-lived enzyme-detecting capability of this ligand and only show diffuse distribution of the label rather than specific regional distribution of the target enzyme."

In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "This application discloses molecules that overcome the shortcomings of previous radioligands and provide specific and long-lived radioligands for diagnosis and for monitoring treatment effects in AD. These compounds are specific substrates of BuChE and contain atoms that can be efficiently replaced with radioactive atoms in the moiety that is attached to BuChE for a longer period, to facilitate detection by SPECT or PET scanning. Such compounds are of utility in the early diagnosis and treatment of diseases associated with dysregulation of BuChE, including AD and related dementias, multiple sclerosis, and malignant tumors; and can distinguish AD brain from normal brain.

"In certain embodiments, the invention is directed to BuChE ligands having a radiolabeled moiety that remains in contact with the enzyme after enzymatic cleavage, (e.g. hydrolysis), of the ligand. This arrangement allows the radiolabeled moiety to remain in contact with the enzyme for a greater duration.

"The inventions is also directed to administration of therapeutically effective amounts of BuChE ligands which inhibit the enzyme for treatment of diseases associated with dysregulation of BuChE, including AD and related dementias, multiple sclerosis, and malignant tumors to a patient in need thereof.

"It is an object of the invention to provide a compound of Formula I and pharmaceutically acceptable salts, stereo-isomers, polymorphs, metabolites, pro-drugs and combinations thereof:

"##STR00002## wherein R.sub.1 is selected from the group consisting of hydrogen, cyano, fluoro, iodo, alkyl, and aryl; R.sub.2 is selected from the group consisting of hydrogen, alkyl, and aryl; X is selected from the group consisting of CH.sub.2, CH.sub.2O, oxygen, OCH.sub.2, CH.sub.2S, SCH.sub.2, NH, N-alkyl, and N-aryl; Y is an optional spacer group, absent or selected from the group consisting of oxygen, sulfur, NH, N-alkyl, and N-aryl; and Z is selected from the group consisting of alkyl substituted with cyano, fluoro, or iodo and aryl substituted with cyano, fluoro, or iodo. In certain embodiments, R.sub.1 and R.sub.2 are both hydrogen, X is CH.sub.2O, Y is absent, and Z is selected from the group consisting of fluorophenyl, cyanophenyl, and iodophenyl. In certain embodiments, Z is selected from the group consisting of .sup.18F-phenyl, .sup.123I-phenyl, and .sup.131I-phenyl. In certain other embodiments, the compound is (6-oxo-1,6-dihydropyridin-2-yl)methyl 4-.sup.123iodobenzoate.

"It is another object of the invention to provide a compound of Formula II and pharmaceutically acceptable salts, stereo-isomers, polymorphs, metabolites, pro-drugs and combinations thereof:

"##STR00003## wherein R.sub.1 is selected from the group consisting of hydrogen, cyano, fluoro, iodo, aryl, and alkyl; R.sub.2 is selected from the group consisting of hydrogen, alkyl, and aryl; X is selected from the group consisting of CH.sub.2, CH.sub.2O, oxygen, OCH.sub.2, CH.sub.2S, SCH.sub.2, NH, N-alkyl, and N-aryl; Y is an optional spacer group, absent or selected from the group consisting of oxygen, sulfur, NH, N-alkyl, and N-aryl; and Z is selected from the group consisting of alkyl substituted with cyano, fluoro, or iodo and aryl substituted with cyano, fluoro, or iodo. In certain embodiments, R.sub.1 and R.sub.2 are hydrogen, X is CH.sub.2O, Y is absent, and Z is selected from the group consisting of cyanophenyl, fluorophenyl, and iodophenyl. In certain other embodiments, Z is selected from the group consisting of .sup.18F-phenyl, .sup.123I-phenyl, and .sup.131I-phenyl. It is another object of the invention to provide a compound of Formula III and pharmaceutically acceptable salts, stereo-isomers, polymorphs, metabolites, pro-drugs and combinations thereof:

"##STR00004## wherein R is selected from the group consisting of alkyl, alkyl-I, alkyl-F, alkyl-CN, aryl-I, aryl-CN, and aryl-F; X is an optional spacer group, absent or selected from the group consisting of oxygen, NH, N-alkyl, and N-aryl; Y is an optional spacer group, absent or selected from the group consisting of oxygen, sulfur, NH, N-alkyl, and N-aryl; and Z is selected from the group consisting of cyano, fluoro, and iodo. In certain embodiments, R is alkyl, X is oxygen, Y is absent or NH, and Z is selected from the group consisting of cyano, fluoro, and iodo. In certain other embodiments, Z is selected from the group consisting of .sup.18F, .sup.123I, and .sup.131I.

"It is another object of the invention to provide a compound of Formulas IVa and IVb and pharmaceutically acceptable salts, polymorphs, metabolites, pro-drugs and combinations thereof:

"##STR00005## wherein R is selected from the group consisting of alkyl, alkyl-I, alkyl-F, alkyl-CN, aryl-I, aryl-CN, and aryl-F; X is an optional spacer group, absent or selected from the group consisting of oxygen, NH, N-alkyl, and N-aryl; Y is an optional spacer group, absent or selected from the group of oxygen, sulfur, NH, N-alkyl, and N-aryl; and Z is selected from the group of cyano, fluoro, and iodo. In certain embodiments, R is alkyl, X is oxygen, Y is absent, and Z is selected from the group consisting of iodo and cyano. In certain other embodiments, Z is selected from the group consisting of .sup.18F, .sup.123I, and .sup.131I.

"It is another object of the invention to provide a method of early detection of a neurological condition, comprising administering to a subject an effective quantity of a butyrylcholinesterase-specific compound; imaging the brain of said subject to identify the position and relative abundance of said compound in vivo utilizing a scan selected from the group consisting of CT, PET, and SPECT; and distinguishing said position and relative abundance from reference cases to determine subject's diagnosis. In certain embodiments, the butyrylcholinesterase-specific compound is the compound of formula I and pharmaceutically acceptable salts, stereo-isomers, polymorphs, metabolites, pro-drugs and combinations thereof. In certain other embodiments, the butyrylcholinesterase-specific compound is (6-oxo-1,6-dihydropyridin-2-yl)methyl 4-.sup.123iodobenzoate. In certain embodiments, the butyrylcholinesterase-specific compound is the compound of formula II and pharmaceutically acceptable salts, stereo-isomers, polymorphs, metabolites, pro-drugs and combinations thereof. In certain embodiments, the butyrylcholinesterase-specific compound is the compound of formula III and pharmaceutically acceptable salts, stereo-isomers, polymorphs, metabolites, pro-drugs and combinations thereof. In certain embodiments, the butyrylcholinesterase-specific compound is the compound of formula IV(a) and pharmaceutically acceptable salts, polymorphs, metabolites, pro-drugs and combinations thereof. In certain embodiments, the butyrylcholinesterase-specific compound is the compound of formula IV(b) and pharmaceutically acceptable salts, polymorphs, metabolites, pro-drugs and combinations thereof.

"In accordance with any of the above objects, the invention is also directed to method in which the neurological condition is Alzheimer's disease and related dementias. In certain other embodiments, the neurological condition is multiple sclerosis. In certain other embodiments, the neurological condition is malignant brain tumor. In certain other embodiments, the subject is a human.

"In accordance with any of the above objects, the invention is also directed to method in which the butyrylcholinesterase-specific compound is radiolabeled on a functional group of the compound that remains in contact with the BuChE after enzymatic cleavage of the compound

"It is another object of the invention to provide a method of treatment of a neurological condition, comprising:

"administering to a subject in need thereof, an effective quantity of a butyrylcholinesterase-specific compound. In certain embodiments, the butyrylcholinesterase-specific compound is the compound of formula I and pharmaceutically acceptable salts, stereo-isomers, polymorphs, metabolites, pro-drugs and combinations thereof. In certain other embodiments, the butyrylcholinesterase-specific compound is (6-oxo-1,6-dihydropyridin-2-yl)methyl 4-iodobenzoate. In certain embodiments, the butyrylcholinesterase-specific compound is the compound of formula II and pharmaceutically acceptable salts, stereo-isomers, polymorphs, metabolites, pro-drugs and combinations thereof. In certain embodiments, the butyrylcholinesterase-specific compound is the compound of formula III and pharmaceutically acceptable salts, stereo-isomers, polymorphs, metabolites, pro-drugs and combinations thereof. In certain embodiments, the butyrylcholinesterase-specific compound is the compound of formula IV(a) and pharmaceutically acceptable salts, polymorphs, metabolites, pro-drugs and combinations thereof. In certain embodiments, the butyrylcholinesterase-specific compound is the compound of formula IV(b) and pharmaceutically acceptable salts, polymorphs, metabolites, pro-drugs and combinations thereof.

"In accordance with any of the above objects, the invention is also directed to method in which the neurological condition is Alzheimer's disease and related dementias. In certain other embodiments, the neurological condition is multiple sclerosis. In certain other embodiments, the neurological condition is malignant brain tumor. In certain other embodiments, the subject is a human.

"In accordance with any of the above objects, the invention is also directed to method in which the butyrylcholinesterase-specific compound is an inhibitor of butvrvlcholinesterase."

For more information, see this patent: Darvesh, Sultan; Joy, Eric; Martin, Earl; Macdonald, Ian; Pottie, Ian. Butyrylcholinesterase Ligands as Diagnostic Tools and Treatment for Diseases of the Nervous System. U.S. Patent Number 8795630, filed August 28, 2009, and published online on August 5, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8795630.PN.&OS=PN/8795630RS=PN/8795630

Keywords for this news article include: Gases, Sulfur, Elements, Hydrogen, Chalcogens, Inorganic Chemicals, Enzymes and Coenzymes, Treventis Corporation.

Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC


For more stories covering the world of technology, please see HispanicBusiness' Tech Channel



Source: Life Science Weekly


Story Tools






HispanicBusiness.com Facebook Linkedin Twitter RSS Feed Email Alerts & Newsletters