Dopamine and serotonin transporter ligands and imaging agents

Details Dopamine and serotonin transporter ligands and imaging agents Dopamine and serotonin transporter ligands and imaging agents

1996-05-17

2001-06-05

Jones, Dameron L. (Department: 1619)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001110, C424S001370, C424S009100, C534S014000, C546S124000, C546S132000

Reexamination Certificate

active

06241963

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel tropane-based ligands that display selective binding to central nervous system receptors, such as dopamine and serotonin transporters (reuptake sites), and have utility, inter alia, as imaging agents for the central nervous system. Also within the scope of this invention are methods for utilizing these ligands as diagnostic agents. Methods for preparing the novel ligands of the invention and intermediates useful in their preparation are also presented.
BACKGROUND
Neural transmitters are chemicals in the brain that are used to send messages from one brain cell to another. Neurotransmitters bind to special receptor proteins in the membranes of nerve cells, like a lock in a key, triggering a chemical reaction within the cell. Dopamine is an example of a central nervous system (CNS) neurotransmitter.
Dopamine is a catecholamine belonging to a class of biogenic amine neurotransmitters, along with norepinephrine, serotonin, and histamine. The catecholomines (particularly dopamine and serotonin) are involved in the control of movement; mood; attention; and possibly, certain endocrine, cardiovascular, and stress responses. Imbalances in neurotransmitter production have been implicated in a variety of mental and physical disorders, such as Parkinson's disease (PD). It is thus desirable to diagnose and monitor such imbalances and to monitor the effectiveness of drugs and substances that affect brain chemistry.
New and powerful imaging methods that enable one to assess the living brain in vivo and thereby monitor brain chemistry and the effectiveness of drugs and substances that affect brain chemistry have been developed. Methods such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) involve administering to a patient a radioactive tracer substance comprising a ligand that binds to the presynaptic or postsynaptic neuroreceptors in the patient's brain. Emissions (primarily gamma rays are emitted from the positrons or photons from the radioactive tracer) are measured. These emissions are indicative of the number and degree of occupancy of blocking of the neuroreceptors. The number of neuroreceptors and the degree of occupancy or blocking is calculated utilizing a mathematical model, and compared with an intra-person or inter-person control to determine the degree of drug response. Further treatment of the patient with drugs is based on the comparisons made. For these methods to be useful, however, a ligand that has a high specificity and affinity for the desired receptor is required.
It is believed that certain radioactive ligands may be selective for dopamine transporters and are thus potentially useful in evaluating changes in dopamine function in vivo and in vitro, especially for patients with Parkinson's disease (PD), which is characterized by a selective loss of dopamine neurons in the basal ganglia and substantia nigra. Recently, a large number of dopamine transporter imaging agents based on cocaine or its closely related congeners, tropane derivatives, have been reported. (Carroll, F. I., et al,
Med. Res. Rev
. 1995, 15, 419-444; Carroll, F. I., et al.,
J. Med. Chem
. 1994, 37, 2865-2873; Carroll, F. I., et al.,
J. Med. Chem
. 1995, 38, 379-388). The regional brain distribution of cocaine is largely concentrated in the basal ganglia, where the dopamine neurons are located. [
11
C]-N-methyl labeled cocaine (Yu, D.-W., et al.,
J. Med. Chem
. 1992, 35, 2178-2183; Fowler, J. S., et al.,
Synapse
1992, 12, 220-227) is a very useful PET (positron emission computed tomography) ligand for studying the pharmacology and drug effects of cocaine itself; however, additional modifications on the cocaine molecule have led to development of positron emission tomography (PET) imaging agent, CFT (WIN35,428) (Clarke, R. L. et al.
J. Med. Chem
. 1973, 16, 1260-1267; Clarke, R. L. et al.
J. Med. Chem
. 1978, 21, 1235-1242; Frost, J. J., et al.,
Ann. Neurol
. 1993, 34, 423-431; Wong, D. F., et al.,
Synapse
1993, 15, 130-142), and single photon emission computed tomography (SPECT) imaging agents &bgr;-CIT (Innis, R. B., et al.,
Proc. Natl. Acad. Sci. U.S.A
. 1993, 90, 11965-11969; Seibyl, J. P., et al.,
J. Nucl. Med
. 1996, 37, 222-228; Kuikka, J. T., et al.,
Eur. J. Nucl. Med
. 1995, 22, 682-686; Neumeyer, J. L., et al.,
J. Med. Chem
. 1994, 37, 1558-1561.), IPT (Goodman, M. M. et al.
J. Med. Chem
. 1994, 37, 1535-1542; Mozley, P. D., et al.,
J. Nucl. Med
. 1996, 37, 151-159), and other related derivatives that display much higher binding affinity and selectivity to dopamine reuptake sites. Both of the agents for PET and SPECT imaging displayed excellent specific uptake in the striatum (basal ganglia) area and are more suitable than GBR12,935 in imaging dopamine reuptake sites (dopamine transporters). (Kilbourn, M. R.,
Life Sci
. 1988, 42, 1347-1353). The dopamine reuptake site ligands are useful in evaluating changes in dopamine reuptake sites in vivo and in vitro, especially for patients with PD. Recent publications describing the use of [
11
C]-CFT (WIN35,428) (Frost, J. J., et al.,
Ann. Neurol
. 1993, 34, 423-431) and [
123
I]-&bgr;-CIT (Innis, R. B., et al.,
Proc. Natl. Acad. Sci. U.S.A
. 1993, 90, 11965-11969; Innis, R. B.,
Eur. J. Nucl. Med
. 1994, 21, 1-5) suggest a strong correlation between the decrease in localization of dopamine transporters in the anterior putamen area and PD symptoms.
Currently, PET and SPECT imaging studies of dopamine transporters are under investigation. Recent publications using [
11
C]-CFT and [
123
I]-&bgr;-CIT suggest a strong correlation between the decrease in localization in the anterior putamen area and PD symptoms. See Innis, R. B. et al.
Proc. Natl. Acad. Sci. U.S.A
. 1993, 90, 11965-11969; Innis, R. B.
Eur. J. Nucl. Med
. 1994, 21, 1-5; Frost, J. J. et al.
Ann. Neurol
. 1993, 34, 423-431, the disclosures of which are herein incorporated by reference in their entirety.
Central nervous system (CNS) receptor function has also been successfully evaluated in vivo using C
11
(T
½
=20 minutes, &bgr;+) or F
18
(T
½
=120 minutes, &bgr;+) labeled agents for positron emission tomography (PET) imaging and
123
I (T
½
=13 hours, 159 KeV) labeled agents for single photon emission computed tomography (SPECT) imaging. See Eckelman, W. C.
Nucl. Med. Biol
. 1992, 18, iii-v; Fowler, J. S. et al.
Ann. Rep. Med. Chem
. 1989, 24, 277-286; Fowler, J. S. et al.
Ann. Rep. Med. Chem
. 1990, 25, 261-268, the disclosures of which are herein incorporated by reference in their entirety.
A ligand that is being widely investigated as an agent for diagnosing and treating PD patients is [
123
I]-CIT. However, one of the drawbacks of [
123
I]-&bgr;-CIT is the length of time (>18 hours) required for reaching optimal uptake ratio in the target area (semi-equilibrium state) (the basal ganglia (BG)) versus the nontarget area (the frontal cortex (CTX)). Because of the need for agents with faster equilibrium times, new ligands such as [
123
I]-IPT (N-(3-iodopropen-2-yl)-2&bgr;-carbomethoxy-3&bgr;-(4-chlorophenyl)tropane) and [
123
I]-&bgr;-CIT-FP are under investigation, both of which reach equilibrium in less than one hour. See Kung, M.-P. et al.
Synapse
1995, 20, 316-324; Malison, R. T. et al.
J. Nucl. Med
. 1995, in Press; Mozley, P. D. et al.
J. Med. Chem
. 1994, 37, 1558-1561, the disclosures of which are herein incorporated by reference in their entirety.
Despite the success in developing such new techniques using PET and SPECT for imaging CNS receptors, their use in routine procedures is hampered by the cost ([
123
I] costs about $30/mCi) and the limited supply of the three isotopes mentioned above,
123
I,
11
C, and
18
F, all of which are produced by cyclotron.
A radionuclide that is widely used in diagnostic nuclear medicine is technetium [
99m
Tc] (T
½
=6 hours, 140 KeV

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