Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-22
2003-02-04
Chang, Ceila (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S193000, C546S232000, C546S233000, C546S234000
Reexamination Certificate
active
06515131
ABSTRACT:
TECHNICAL FIELD
The present invention is directed to central nervous system dopamine transporter-imaging agents, and more particularly, to labeled piperidine derivatives for use as imaging agents in the diagnosis of Parkinson's disease.
BACKGROUND OF THE INVENTION
Each year approximately 50,000 Americans are diagnosed with Parkinson's disease with the estimated total cost to the US economy exceeding $5.6 billion annually. There exists no known test for Parkinson's Disease (PD) and current diagnosis relies on observations of the symptoms relating to deteriorating muscular control. With the difficulties in early diagnosis and no known causes, except for age or head trauma, the need for improved screening and treatment in our aging population continues to grow. While it has been demonstrated that disease progression can be monitored non-invasively in vivo by PET,
1,2
the inaccessibility and cost of PET make such screening ineffective. The availability of a radiolabeled dopamine transporter (DAT) ligand for imaging with single photon emission computed tomography (SPECT) would bring this capability to the majority of the population. Performing such brain imaging studies not only creates the possibility to follow the degeneration rate of the dopaminergic neurons in Parkinson's disease, but also provides an opportunity to estimate therapeutic effects of putative neuro-protective agents in individual patients.
3
Hence, an inexpensive and widely available agent for imaging DAT is warranted.
The development of radiolabeled ligands for SPECT imaging of the DAT has been difficult. Successful imaging of DAT in primates and humans has been demonstrated using several I-123-labeled analogs of the WIN 35,428 series of cocaine analogs.
4-6
However, the US market has yet to embrace Iodine-123 to the extent that there exists a commercially reliable and cost effective supply of this isotope. Tc-99m an inexpensive and more readily available isotope with ideal imaging characteristics for SPECT has enjoyed limited success as a radiolabel for DAT ligands. Kung et al, have demonstrated the technical feasibility of imaging DAT using TRODAT, a Tc-99m labeled tropane analog.
7,8
While a notable achievement, absolute brain uptake with this agent is very low resulting in less than ideal image quality. Structure activity studies to predict brain uptake with this series of ligands has proved to be less than reliable, suggesting the molecular size of the ligands is on the threshold for being able to cross the blood brain barrier efficiently. Kung et al have recently reported the dramatic effects of changes in the length of the carbon spacer unit in a tropane series of Tc-99m complexes.
9
Increasing the spacer length between the chelate and the tropane moeity from one to two carbons, while maintaining good transporter binding, resulted in little if any brain accumulation.
The National Parkinson's Foundation estimates that 1.5 million Americans are affected by Parkinson's disease (PD). While it is important to realize that PD is not a fatal disease, it is a crippling, degenerative disease with no cure. PD is a slowly progressive disease that affects a small area of cells located in the area of the brain known as the substantia nigra. The degeneration of these cells causes a reduction in a vital neurotransmitter involved in muscle activity (among other functions) called dopamine. The lack of dopamine causes a wide range of muscle misfunction but the four primary symptoms are tremors, rigidity, bradykinesia (slowness of movement) and postural instability. The disease is generally considered to target older adults, affecting 1 out of every 100 people over the age of 60.
Currently there is no known test available to diagnose a person with Parkinson's. The physician has to observe the symptoms until it is apparent that Parkinson's disease is present. Even with an experienced physician, an early, accurate diagnosis is difficult, especially with the many different forms of the disease, all treated with slightly different medications. The treatment of PD (the most common form of Parkinsonism) includes a delicate balance of medications, (usually the anticholinergic amantadine to start, follow by levodopa with cabidopa, Selegiline™, Bomocriptine™, or Perogolide™), allied health interventions (physical, occupational, and speech therapies) as well as new experimental procedures (thalamotomy to relieve tremors, Diacrin's fetal cell implants-NeuroCell™, or Guilford's neuroimmunophilin technology
11
). The list of medications for PD is extensive with all of the drug combinations possessing advantages and disadvantages. Evaluation is usually done on an individual basis in an attempt to minimize the potential side effects which include nausea, low blood pressure, involuntary movements, and restlessness, to name a few. The disease management is made more complex when one takes into account the “wearing-off” phenomenon and the “on-off” effects which commonly occur with these medications. With numerous drug combinations currently employed, countless new drugs coming through clinical trials (i.e. new dopamine agonists, Requip™ and Mirapex™), and the expense of new implantation procedures, it would be a great asset to be able to evaluate these potential treatments.
SUMMARY OF THE INVENTION
Generally, the present invention is directed to central nervous system dopamine transporter-imaging agents and methods of use thereof. In certain embodiments, the present invention relates to radiolabeled piperidine derivatives for use as imaging agents in the diagnosis of Parkinson's disease. Another aspect of the present invention relates to piperidine monoamine transporter ligands, comprising a functional group capable of chelating a radionuclide, e.g., technetium, and methods of use thereof.
DETAILED DESCRIPTION OF THE INVENTION
The main focus of our attention addresses the opportunity to improve detection and management of PD, we realize the other potential applications of our technology. Two other large potential markets concern cocaine abuse monitoring
12
and attention deficit hyperactivity disorders (ADHD/ADD). According to the National ADD Association millions of children (4-6% of the US population) are treated, and many overtreated, for the complex conditions of ADHD/ADD. The diagnostic criteria are lengthy and complex, often leading parents and doctors to clinically erroneous conclusions. We believe a definitive test would minimize the confusion, decrease unnecessary drug use, guide appropriate treatment, and monitor existing medications of the commonly prescribed Ritalin™, Dexedrine™, and Adderall™. The recent correlation established between ADD and mutations of the dopamine transporter gene
13
further demonstrates the need for a DAT-imaging agent.
One approach to developing new method for treatment of Parkinson's Disease involves investigating the piperidine nucleus, while maintaining the functional integrity of the system and the established chemistry of the N
2
S
2
chelator. Based on our proprietary work we have developed the ability to rationally design DAT, SERT, and NET selective ligands by employing different isomeric forms, or other synthetic modifications.
10
Our proprietary position allows us to build upon the many recent successes in the field. Herein, we propose to synthesize and label a series of novel piperidine monoamine transporter ligands with technetium-99m, prepare the corresponding rhenium analogs, analyze their in vitro pharmacology, examine the in vivo localization properties, and evaluate their potential as specific tracers for the dopamine transport system. The new technetium imaging agents would improve initial diagnosis, as well as track the effects of potential therapeutic regiments in PD management.
In particular, one approach is to synthesize a series of novel piperidine monoamine transporter ligands, including separation and purification of all cis/trans isomers. Then prepare the corresponding rhenium-piperidine analogs, including separat
Babich John W.
Smith Miles P.
Biostream Therapeutics, Inc.
Chang Ceila
Foley & Hoag LLP
Gordon Dana M.
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