Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1999-11-08
2002-07-09
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001850, C424S001890
Reexamination Certificate
active
06416735
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to new ligands for nicotinic acetylcholine receptors (nAChRs), particularly radioligands and fluorimetric ligands based on methyllycaconitine (MLA).
2. Discussion of the Background
Neuronal nicotine acetylcholine receptors (nAChRs) represent a major neurotransmitter receptor superfamily responsible for excitatory neurotransmission (Lindstrom et al.
Ann. N. Y. acad Sci.,
1995, 757, 100-116). The &agr;4&bgr;n and &agr;7 nAChR are the major receptors in the human brain. These receptors are of great interest since they appear to play a critical role in tobacco dependence and neurodegenerative disease. In particular, the nAChRs have been targeted for the development of drugs for cognitive function, Parkinson's disease, analgesia, inflammatory bowel disorder, schizophrenia, anxiety, depression, Tourette's syndrome and smoking cessation. For example, the addictive nature of cigarette smoking can be attributed to the reinforcing properties of nicotine (Corrigall et al.
Psychopharmacology,
1992, 107, 285-289), and nicotine, which binds to nAChRs with high affinity, has been utilized in various smoking cessation therapeutics (Balfour et al.
Pharmacol. Ther.,
1996, 72, 51-81). In post-mortem autoradiographic studies on Alzheimer's disease tissue, several groups have consistently revealed significant reduction of nAChRs in comparison to controls (Whitehouse et al.
Brain Res.,
1986, 371, 146-151; Nordberg et al.
Neurosci. Lett.
1986, 72, 115-119; London et al.
Neurochem. Res.,
1989, 14, 745-750). In addition, nicotine appears to improve cognitive functions (Lippielo
Alzheimer's Disease. Therapeutic Strategies,
1994, E. Giacobini and R. Bekcer, Ed., Boston, Birkhauser, 186-190). These results have prompted the pharmaceutical industry to explore the development of safe and effective nAChR-based therapeutic agents for treatment of Alzheimer's disease (Brioni et al.
Adv. Pharmacol.,
1997, 37, 153-214).
Over the past few years considerable effort has been directed toward the identification and characterization of radioligands for nicotinic acetylcholine receptors (nAChRs) (Holladay et al,
J. Med. Chem.
1997, 40, 4169-4194). Two major classes of nicotinic receptors have been identified in rat and human brain based on whether they demonstrate high affinity binding for either [
3
H]nicotine or [
125
I]&agr;-bungarotoxin ([
125
I]&agr;-BGT) (Marks et al,
Mol. Pharmacol.
1982, 22, 554-564. Heteromeric receptors composed of &agr; and &bgr; subunits bind [
3
H]nicotine with high affinity. The &agr;4&bgr;2 receptor is the most common subtype comprising almost 90% of rat brain nAChRs (Lindstrom et al,
Ciba Found Symp.
1990, 152, 23-52). Receptors with high affinity for [
125
I]a-BGT contain only the &agr;7 subunit (Clarke et al,
J. Neurosci.
1985, 5, 1307-1315; Seguela et al,
J. Neurosci.
1993, 13, 596-604) and display a regional distribution distinct from the &agr;&bgr; heteromeric receptors (Marks et al,
Mol. Pharmacol.
1982, 22, 554-564; Marks et al,
Mol. Pharmacol.
1986, 30, 427-436). Several new tritium and iodine-125 ligands have been developed for studying the pharmacological properties of &agr;4&bgr;2 nAChRs (Houghtling et al,
Mol. Pharmacol.
1995, 48, 280-287; Davila-Garcia et al,
J. Pharmacol Exp. Ther.
1997, 282, 445-45 1; Horti et al,
Nucl. Med. Biol.
1999, 26, 175-182; Musachio et al,
Synapse
1997, 26, 392-399; Musachio et al,
Life Sci.
1998, 62, PL 351-357; Scheffel et al,
NeuroReport
1995, 6, 2483-2488.). In addition, several carbon-11, fluorine-18, and iodine-123 positron emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers have been developed for in vivo imaging of &agr;4&bgr;2 nAChRs (Horti et al,
Nucl. Med. Biol.
1999, 26, 175-182; Musachio et al,
Synapse
1997, 26,392-399; Musachio et al,
Life Sci.
1998, 62, PL 351-357; Ding et al,
Synapse
1996, 24, 403-407; Ding et al, Mapping nicotinic acetylcholine receptors with PET, Society for Neuroscience, Washington, D.C., 1996, Abstract 22, 269; Horti et al,
J. Labelled Compd. Radiopharm.
1996, 38, 355-365; Ding et al,
Nucl. Med. Biol.
1999, 26, 139-148; Gatley et al,
Nucl. Med. Biol.
1998, 25, 449-454; Ding et al,
J. Label Compds. Radiopharm.
1997, 39, 827-832; Liang et al,
J. Med. Chem.
1997, 40, 2293-2295; Loc'h et al,
J. Labelled Compd. Radiopharm.
1997, 40, 519-521; Patt et al,
Nucl. Med. Biol.
1999, 26, 165-173; Dolle et al,
J. Med. Chem.
1999, 42, 2251-2259; Dolci et al,
Bioorg. Med. Chem.
1999, 7, 467-479; Horti et al,
J. Labelled Comp. Radiopharm.
1998, 41, 309-318; Horti et al,
J. Med. Chem.
1998, 41, 4199-4206; Horti et al,
Nucl. Med. Biol.
1998, 25, 599-603). At present, [
125
I]-&agr;-BGT is the only iodine-labeled radioligand specific for the &agr;7 nAChR. &agr;-BGT is a 7800-8000 kD 74 amino acid polypeptide isolated from snake venom,
Bungarus multicinctus
(Mebs et al,
Became. Biophys. Res. Commun.
1971, 44, 711-716.) The radioligand has the disadvantage of big nonspecific binding in filtration-based assays. Moreover, &agr;-BGT does not cross the blood-brain barrier limiting its use for imaging studies for the &agr;7 nAChR.
Neuronal [
125
I]&agr;-BGT binding sites, a subtype of nicotinic receptors, are altered in a number of CNS disorders such as schizophrenia and Parkinson's disease (Freedman et al.
Proc. Natl. Acad. Sci. USA,
1997, 94, 587-592). A good correlation has been noted between the distribution of &agr;7 mRNA subunits and that of the high affinity binding sites for &agr;-BGT in rodent brain (Clarke et al.
J. Neurosci.,
1985, 5, 1307-1315; Seguela et al.
J. Neurosci.,
1993, 13, 596-604). However, potent and selective agonists and antagonists at the &agr;7 nicotinic receptor subtype are lacking. Methyllycaconitine (MLA), a natural product isolated from the seeds of
Delphinium brownii,
has high affinity to neuronal [
125
I]&agr;-BGT binding sites (K
i
=4 nM), in contrast to its much weaker interactions with the &agr;-bungarotoxin-sensitive nicotinic receptor subtype present on the neuromuscular junction and with other nicotinic receptor subtypes labeled by [
3
H]nicotine. MLA blocked the activation of &agr;7 receptor subtype expressed in oocytes with an IC
50
in the picomolar range (Palma et al.
J. Physiol.,
1996, 491, 151-161). The selectivity of MLA towards the brain &agr;-bungarotoxin-sensitive receptor subtype, i.e. &agr;7, makes this agent very useful for studying the properties of this subtype in vitro. In contrast to &agr;-BGT, MLA is a relatively small reversible binding compound. In addition, Turek et al (Turek et al.
J. Neurosci. Meth.
1995. 61, 113-118) showed that peripherally administered MLA crosses the blood-brain barrier and may, therefore, be a useful tool to further probe the CNS functions of the &agr;7 nicotinic receptor subunit in vivo.
In general, imaging drug and neurotransmitter receptors by PET or SPECT is very useful. For example, dopamine transporters can be imaged, and this procedure shows great promise as a diagnostic approach for Parkinson's disease (Kuhar et al.
Neurotransmitter Transporters: Structure and Function,
1997, M. E. A. Reith, Ed., Totowa, N.J., Human Press, Publishers, 297-313; Innis et al.
Proc. Natl. Acad Sci. USA,
1993, 90, 11965-11969; Frost et al.
Ann. Neurol.,
1993, 34, 423-431) as a method to determine the doses of therapeutic drugs needed to achieve significant receptor occupancy and, therefore, therapeutic benefit (Scheffel et al.
Synapse,
1994, 16, 263-268) and as a method to reflect the level of neurotransmitter present in the synapse and the activity of central cholinergic systems (Volkow et al.
Synapse,
1994, 16, 255-262).
Tomographic imaging studies of central nAChRs in living subjects have been hampered by the absence of radiotracers that possess favorable in vivo properties. Although [C-11](−)ni
Abraham Philip
Carroll Frank Ivy
Navarro Hernán A.
Zhong Desong
Hartley Michael G.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Research Triangle Institute
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