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Boat tropanes

a technology of tropanes and boats, applied in the field of coordination complexes, can solve the problems of reducing striatal contrast, difficult to produce metal chelates which can cross the blood brain barrier, and difficult to quantify da

Inactive Publication Date: 2007-01-11
PRESIDENT & FELLOWS OF HARVARD COLLEGE +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0023] The imaging agents of the present invention are useful for detecting tropane recognition sites including neuronal transporters such as the dopamine transporter. For purposes of the present invention, a tropane recognition site is any receptor or transporter site that binds to the tropane compound. Thus, the compounds of this invention can be used as diagnostic agents, prognostic agents and therapeutic agents for neurodegenerative diseases.
[0024] The present invention also provides a method of using the coordination complex as an imaging agent for detecting neurodegenerative and neuropsychiatric disorders characterized by a change in density of DAT or dopamine neurons. For example, a method for detecting the change in DAT resulting from a neurodegenerative disease, suc

Problems solved by technology

Yet, it has been difficult to produce a metal chelate which can cross the blood brain barrier while still retaining binding affinity and selectivity for its receptor site.
Although such a nontarget binding typically poses no serious problem in the imaging of normal brains due to the greater number of DAT compared to SET, under disease conditions in which DAT are selectively reduced (or in which SET may be selectively increased), binding to the SET may make it difficult to quantify DAT.
Moreover, binding to SET in other brain regions such as the hypothalamus and thalamus can reduce striatal contrast and diminish accuracy in localizing and imaging the striatum.
However, a number of difficulties arise in the use of technetium for radioimaging agents because of its chemistry.
Consequently it is much more difficult to design and prepare a 99mTc radioligand than it is to prepare a radioligand using other radionuclides such as 123I, which can be attached covalently to the ligand.
The size of the chelating agent for technetium also can create problems when using this radionuclide in imaging agents.
This can be an especially difficult problem when attempting to design receptor-based imaging agents using Tc.
Although the tropane family of compounds are known to bind to the dopamine transporter, the addition of bulky chelating ligands for binding technetium or rhenium would be expected to affect potency and ability to cross the blood brain barrier of the resulting labeled complex.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

(1R)-2-(Methoxycarbonyl)-3-[[(trifluoromethyl)sulfonyl]oxy]trop-2-ene (Compound 2, FIG. 2)

[0087] (1R)-(−)-2-Methoxycarbonyl-3-tropinone, 1 {Meltzer et al., J. Med. Chem, 1994, 37, 2001} (1 g, 5.07 mmol) was dissolved in anhydrous THF (20 mL) and the resulting solution cooled to −78° C. A solution of sodium bistrimethylsilylamide (1 M, 5.58 mL, 5.58 mmol) was then added to the solution slowly. After 30 min, N-phenyltrifluoromethane sulfonamide (1.94 g, 5.43 mmol) was added. The resulting solution stirred for a further 45 min at −78° C. and then allowed to attain room temperature and stirred at room temperature for 2 h. All solvent was evaporated and the residue pumped to dryness. Column chromatography was performed on the residue (SiO2 60 g; 2%-16% methanol in ethyl acetate) and gave 1.62 g (97%) of a yellow oil which crystallized on standing.

[0088] Rf 0.65 (10% MeOH / EtOAc). 1H-NMR (CDCl3) δ 1.58 (m, 1H), 1.97 (m, 2H), 2.1-2.2 (m, 2H), 2.39 (s, 3H). 2.84 (dd, J=18, 4 Hz, 1H), 3.42 ...

example 2

(1R)-N-Methyl-2-methoxycarbonyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene (Compound 3, FIG. 2)

[0089] (1R)-2-Methoxycarbonyl-3-[[(trifluoromethyl)sulfonyl]oxy] tropene 2 (620 mg, 1.88 mmol), LiCl (171 mg, 4.03 mmol), Pd2dba3 (69 mg, 0.075 mmol), aq. Na2CO3 (2.0 M, 2 mL), diethoxymethane (6.2 mL) were all charged to a flask and stirred vigorously. To this solution was added 3,4-dichlorophenyl boronic acid (474 mg, 2.49 mmol). The reaction was then brought to reflux for 2 h and filtered through celite. The cake was washed with ether and the organic solution was washed with concentrated NH4OH. The washed solvent was dried with K2CO3, filtered, and evaporated. The residue was charged to a column (SiO2, 60 g, eluted with 5-6% Et3N / EtOAc) and gave 512 mg (83%) of a yellow oil which solidified upon standing.

[0090] Rf 0.56 (10% Et3N / EtOAc). IR (KBr) 2941, 1724, 1460, 1418, 1333, 1250, 1212, 1124 cm−1. 1H-NMR (CDCl3) δ 1.61 (m, 1H), 1.9-2.05 (m, 2H), 2.1-2.3 (m, 2H), 2.43 (s, 3H),...

example 3

(1R)-N-Methyl-2β-methoxycarbonyl-3β-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane (Compound 4 (R=3,4-Cl2), FIG. 2), and

(1R)-N-Methyl-2β-methoxycarbonyl-3α-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane (Compound 12 (R=3,4-Cl2), FIG. 2)

[0091] To (1R)-N-Methyl-2-methoxycarbonyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene, 3 (4 g, 12.3 mmol) in THF (43 mL) at −78° C. was added SmI2 solution (0.1 M in THF, 400 mL, 40 mmol) dropwise. After 30 min at −78° C., MeOH (140 mL) was added and the resulting solution stirred at −78° C. for a further 1 h. The reaction was then quenched with TFA (28 mL) and water (285 mL), the cold bath was removed and the solution allowed to attain room temperature. The reaction was then made basic with NH4OH and diluted with ether and filtered through celite. The filter cake was washed with ether and all the organic phases were combined and washed with a sodium thiosulfate solution and then a brine solution. After drying with Na2SO4 the solution was fi...

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Abstract

Radiopharmaceutical compounds are disclosed. A tropane compound is linked through the N atom at the 8-position to a chelating ligand capable of complexing technetium or rhenium to produce a neutral labeled complex that selectively binds to the dopamine transporter over the serotonin transporter with a ratio of 10 or more. These compounds can be prepared as separate diastereoisomers as well as a mixture of diastereoisomers. Also disclosed are radiopharmaceutical kits for preparing the labeled radiopharmaceutical compounds.

Description

FIELD OF THE INVENTION [0001] The present invention relates to coordination complexes comprising a radiolabeled ligand with high binding affinity and good selectivity for the dopamine transporter (DAT). Such agents can be useful for the early diagnosis and treatment of neurodegenerative disorders. BACKGROUND OF THE INVENTION [0002] The dopamine transporter (DAT) plays a critical role in physiological, pharmacological and pathological processes in brain. The transport system is a primary mechanism for terminating the effects of synaptic dopamine, thereby contributing to the maintenance of homeostasis in dopamine systems. It also appears to be a principal target of cocaine in the brain. (Kennedy and Hanbauer, J. Neurochem. 1983, 41, 172-178; Shoemaker et al., Naunyn-Schmeideberg's Arch. Pharmacol. 1985, 329, 227-235; Reith et al., Biochem Pharmacol. 1986, 35, 1123-1129; Ritz et al., Science 1987, 237, 1219-1223; Madras et al., J. Pharmacol. Exp. Ther. 1989a, 251, 131-141; Bergman et a...

Claims

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Application Information

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IPC IPC(8): A61K51/00C07F13/00C07D451/02A61K31/46A61K51/04A61P25/00A61P25/28A61P43/00
CPCA61K31/46A61K51/0448A61K51/0478A61B6/506C07D451/02C07F13/005A61K51/0497A61P25/00A61P25/28A61P43/00A61K51/00
Inventor T
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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