New Synthetic Variants of 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriamine Pentaacetic Acid (1B4M-DTPA): Novel Macromolecular MRI Contrast Agents
Description of Invention:
The present invention describes the synthesis and use of two protected variants of the 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriamine pentaacetic acid (1B4M-DTPA) (also known as the commercial bifunctional chelator, tiuxetan), bearing either an isothiocyanate or a succinimidyl ester moiety, respectively. These molecules were synthesized for the following uses: (1) use in the introduction of the chelator to the N-terminus of peptides, aptamers, PNA, etc wherein deprotection or cleavage from resin or solid phase support of the product is possible and (2) introduction of the chelator to macromolecular structures such as dendrimer wherein this is accomplished in organic solvents eliminating the gross inefficiency of the prior aqueous methods.
In both uses, the elimination or delay of any aqueous chemistry steps in the synthesis process obviates the possibilities of contamination by spurious metals. Metal contaminations could compromise latter radiolabeling or can also hinder the introduction of paramagnetic ions such as Gd(III) for MRI applications. The chemistry used in this synthetic process is very flexible and provides the basis for an extensive list of conjugation functional groups to be introduced.
Comparative MR imaging with these dendrimer based molecules revealed equivalent enhancement of the vessels and organs such as the kidney and liver.
Applications:
Useful in the conjugation of nearly all peptides for targeting antigens/peptides associated with cancers.
Useful for modification of macromolecules such as dendrimer, carbon tubes, etc., for labeling with radioactive metal ions suitable for imaging and/or therapy and paramagnetics for MRI.
Advantages:
The chemistry is very flexible and provides the basis for an extensive list of conjugation functional groups to be introduced.
The elimination of aqueous chemistry steps obviates the possibilities of contamination by spurious metals that could compromise subsequent radiolabeling.
The elimination of aqueous steps aids in the introduction of paramagnetic ions such as Gd(III) for MRI applications.
The general synthesis process provides a procedure for preparing dendrimer-based MR agents with higher yields and efficiency while enhancing versatility.
Benefits:
In spite of advances in cancer therapeutics and diagnostics, more than 600,000 cancer deaths are estimated to occur in 2007. Early and accurate detection is a key component of successful clinical management of cancer. This technology can contribute to the development of better MRI agents for diagnosing cancer and thus improve overall survival and quality of life of patients suffering from cancer.
Development Status:
Synthesis process and data available.
Patent Status:
DHHS Reference No. E-226-2006/0 --
U.S. Provisional Application No. 60/864,503 filed 06 Nov 2006
PCT Application No. PCT/US2007/083734 filed 06 Nov 2007, which published as WO 2008/070384 on 12 Jun 2008
Relevant Publication: H Xu, CA Regino, M Bernardo, Y Koyama, H Kobayashi, PL Choyke, MW Brechbiel. Toward improved syntheses of dendrimer-based magnetic resonance imaging contrast agents: new bifunctional diethylenetriaminepentaacetic acid ligands and nonaqueous conjugation chemistry. J Med Chem. 2007 Jul 12;50(14):3185-3193. [PubMed abs]
Portfolios: Devices/Instrumentation Cancer
Cancer -Diagnostics-In Vivo-Conjugate Chemistry Devices/Instrumentation-Diagnostics-Imaging Cancer -Diagnostics Devices/Instrumentation-Diagnostics
For Additional Information Please Contact: Surekha Vathyam Ph.D.
Office of Technology Transfer
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Phone: 301/435-4076
Email: vathyams@mail.nih.gov
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