Manganese-based magnetic resonance contrast agents

a magnetic resonance imaging and contrast agent technology, applied in the direction of diagnostic recording/measuring, enzyme stabilization, peptides, etc., can solve the problems of insufficient vascularization, affecting the blood supply to the affected area, and often disrupting the regulation, so as to facilitate the preparation of dual mr-pet probes, facilitate the tumbling of molecules, and enhance the mn(ii) relaxivity

Inactive Publication Date: 2015-11-26
CARAVAN PETER +5
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about using MRIs (magnetic resonance imaging) to image the movement of certain molecules in organisms. MRIs can provide 3D information at a high level of detail, making it easy to see changes in cells. The patent also discusses a new technique that uses high molecular weight molecules to enhance the imaging of certain metals in the organism. These molecules can also be labeled with positron emitting isotopes, allowing for the creation of probes that can be detected using both MRIs and positron emission tomography. Overall, the patent suggests that MRIs can provide more accurate and quantitative information about the physiological parameters of the organism.

Problems solved by technology

However, this regulation is often disrupted during periods of cellular stress, damage or cell death.
Some of these probes target tissues that are hypoxic (low oxygen tension), which may result from a disruption in blood supply to the affected area or inadequate vascularization as sometimes occurs in tumors.

Method used

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  • Manganese-based magnetic resonance contrast agents
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  • Manganese-based magnetic resonance contrast agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Experimental

General

[0119]Materials and Instrumentation. All chemicals and solvents were purchased commercially and used without further purification. NMR spectra were recorded on either 500 MHz or 400 MHz Varian spectrometers. Chemical shifts are reported in δ (ppm). For 1H and 13C NMR spectra, the residual solvent peaks were used as internal reference, except for the 13C NMR of the ligand where tertbutanol was used as the internal reference.

[0120]Liquid chromatography-electrospray mass spectrometry (LC-MS) was performed using an Agilent 1100 Series apparatus with an LC / MSD trap and Daly conversion dynode detector with UV detection at 220, 254 and 280 nm. The methods used on this system are as follows: (a) Luna C18 column (100×2 mm); eluent A: H2O / 0.1% formic acid, B: MeCN / 0.1% formic acid; gradient: 5% B to 95% B over 9 minutes; flow rate 0.8 mL / min (used for characterization of organic compounds), and (b) Kromasil C18 column (250×4.6 mm); eluent C: 95% MeCN / 5% 10 mM ammonium aceta...

example 2

Synthesis

[0178]A synthetic scheme for Example 2 can be found in FIG. 34.

N-tosyl diethylenetriamine (32)

[0179]To a batch of 8.480 g (81.71 mmol) diethylenetriamine stirring in 120 mL MeCN at 0° C. was added 1.768 g (9.27 mmol) p-toluenesulfonyl chloride. A white heterogeneous solution formed instantly and the solution was warmed to room temperature and left to stir for 16 hours. The solution was subsequently concentrated to a white oil, taken up in 30 mL H2O, the pH adjusted to >10 and washed 2x with Et2O. The aqueous layer was then concentrated to a white residue via lyophilization. The resultant residue was taken up in 30 mL H2O and the pH adjusted to 7 via careful addition of trifluroacetic acid (TFA). The product was then purified via preparative HPLC using a Restek Ultra Aqueous C18 column (10 mm×250 mm); eluent A: H2O / 0.1% TFA, B: MeCN / 0.1% TFA; gradient 5% to 95% B over 23 minutes; flow rate: 5 mL / min. The fractions containing product were pooled and MeCN and TFA removed via r...

example 3

Synthesis

[0184]Synthetic schemes for Example 3 can be found in FIGS. 38 and 39.

N-benzyl-1,2-diaminocyclohexane (36)

[0185]To a batch of 7.113 g (62.29 mmol) 1,2-diaminocyclohexane in 50 mL MeCN was added dropwise 1.093 g (6.39 mmol) benzyl bromide in 10 mL MeCN at room temperature over the course of 1 hour. After 16 hours, the resultant white, heterogeneous solution was concentrated to dryness and partitioned between CH2Cl2 and satd. Na2CO3(aq). The layers were separated and the organic phase washed again with satd. Na2CO3(aq) then brine, dried over Na2SO4 and concentrated to 1.280 g (6.26 mmol, 98%) of 36 as a light yellow oil. 1H NMR (500 MHZ, CDCl3, δ from TMS): 7.36-7.22 (m, 5H), 3.94 (d, 1H), 3.69 (d, 1H), 2.38 (m, 1H), 2.09 (m, 2H), 1.90 (m, 1H), 1.73 (m, 2H), 1.32.-1.09 (m, 4H). ESI-MS: m / z=205 [M+H]+; calcd.: 205.3.

N′-benzyl-N′,N″,N″-tritbutylacetate-I,2-cyclohexylenediamine (37)

[0186]To 1.133 g (5.55 mmol) 36, 4.194 g (32.35 mmol) diisopropylethylamine and 0.966 g (5.82 mmol...

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Abstract

Manganese coordination complexes with utility as magnetic resonance probes and as biological reductant sensors are disclosed. In one embodiment, ligands can stabilize both the Mn2+ and Mn3+ oxidation states. In the presence of a reductant such as glutathione, low relaxivity MnIII-HBET is rapidly converted to high relaxivity MnII-HBET with a 3-fold increase in relaxivity, and concomitant increase in magnetic resonance signal. In another embodiment, ligands were designed to chelate Mn(ll) in a thermodynamically stable and kinetically inert fashion while allowing for direct interaction of Mn(ll) with water. In yet another embodiment, high molecular weight multimers containing six Mn(ll) chelators were prepared. The high molecular weight results in slower tumbling of the molecules in solution and can strongly enhance the Mn(ll) relaxivity.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application claims priority from U.S. Patent Application No. 61 / 749,614 filed Jan. 7, 2013.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH[0002]This invention was made with government support under grant numbers CA161221 and RR14075 awarded by the National Cancer Institute and National Center for Research Resources. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The invention relates to contrast agents for magnetic resonance imaging. The invention also relates to methods for preparing the contrast agents.[0005]2. Description of the Related Art[0006]When a substance such as human tissue is subjected to a uniform magnetic field (polarizing field B0), the individual magnetic moments of the excited nuclei in the tissue attempt to align with this polarizing field, but precess about it in random order at their characteristic Larmor frequency. If the substance, or tissue,...

Claims

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Application Information

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IPC IPC(8): C07F13/00A61K49/14A61K49/16A61K49/06
CPCC07F13/005A61K49/16A61K49/14A61K49/06A61K49/103A61K51/04A61K49/106A61K51/0455A61B5/055A61B5/0035
Inventor CARAVAN, PETERGALE, ERIC M.LOVING, GALEN S.MUKHERJEE, SHEREYAZHU, JIANG
Owner CARAVAN PETER
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