EDHPA based contrast agents for MR imaging, apparatus and methods

Claim 1

An EDHPA based contrast agent in a solid state form, for use in an in vivo solution during diagnostic magnetic resonance (MR) imaging, to enhance the MR image of the region of interest of a subject within the magnetic field of the MR system, having the general formula: ##STR2## where: "PM" is a paramagnetic metal ion bound by chelation within the EDHPA; "B" is a benzene ring bonded to the acetic carbon, with only the "O - " phenol radical at the ortho position, or, a benzene ring bonded to the acetic carbon, with the "O - " phenol radical plus a para position phenol radical selected from the group consisting of ______________________________________ alkyl: --(CH.sub.2)--CH.sub.3, carboxyl: --COO.sup.-, nitro: --NO.sub.2, and sulfonic acid: --SO.sub.3.sup.- ; ______________________________________ "n" is, from 2 to 4 inclusive, methyl groups within the methyl chain connecting the two Nitrogen atoms; and "IN + " is a chemically inert cation for balancing the charge of the contrast agent molecule; whereby the contrast agent causes a reduction in the T1 relaxation timer near the region of interest within the subject.

Claim 16

A method of manufacture of a chemically stable physiologically tolerable contrast agent EDHPA'(PM) by deprotonating and chelating the corresponding EDHPA based chelator, for use in vivo solution during diagnostic magnetic resonance (MR) imaging, to enhance the MR image of the region of interest of a subject within the magnetic field of the MR system, comprising: PROVIDING INITIAL SOLVENT for the deprotonating and chelating steps; PROVIDING to the solvent EDHPA based chelator having the general form: ##STR4## where: "B" is a benzene ring bonded to the acetic carbon, with only the "OH" phenol radical at the ortho position, or, a benzene ring bonded to the acetic carbon, bonded with the "OH" phenol radical plus a para position phenol radical selected from the group consisting of ______________________________________ alkyl: --(CH.sub.2)--CH.sub.3, carboxyl: --COOH, nitro: --NO.sub.2, and sulfonic acid: --SO.sub.3 H; ______________________________________ and "n" is, from 2 to 4 inclusive, methyl groups within the methyl chain connecting the two Nitrogen atoms; DEPROTONATING THE EDHPA' by adding a strong base deprotonating agent for removing the protons from the four oxygen coordinate sites: ______________________________________ EDHPA Based Chelator Plus Deprotonating Agent EDHPA'(-4) - (H.sup.+).sub.4 4(Dcat.sup.+ Dan.sup.-) Yields Deprotonated EDHPA' Plus Deprotonation By-Product EDHPA'(-4) + 4Dcat.sup.+ 4(H-Dan) (EDHPA' salt) ______________________________________ where: Dan - is a deprotonating anion for pulling the protons away from the EDHPA' chelator, and Dcat + is a deprotonating cation which occupies the four negatively charged coordination points, to provide the EDHPA'(-4) ion in solution; CHELATING THE EDHPA'(-) to form EDHPA'(PM) by adding the paramagnetic metal ion in the form of a metal salt: ______________________________________ Deprotonated EDHPA' Plus Metal Salt EDHPA'(-4) + 4Dcat.sup.+ PM + 2 - 2(Can.sup.-) Yields Chelated EDHPA' Plus Chelation By-Product EDHPA'(PM).sup.-- + 2Dcat.sup.+ 2(Can-Dcat) ______________________________________ where: PM is a paramagnetic metal cation from the added metal salt, and Can - is the counter anion from the added metal salt, to provide the EDHPA based chelator in the contrast agent form of EDHPA'(PM).

Claim 17

A method of manufacture of a chemically stable physiologically tolerable contrast agent EDHPA'(PM) by deprotonating and chelating the corresponding EDHPA based chelator, for use in vivo solution during diagnostic magnetic resonance (MR) imaging, to enhance the MR image of the region of interest of a subject within the magnetic field of the MR system, comprising: PROVIDING INITIAL SOLVENT for the deprotonating and chelating steps; PROVIDING to the solvent EDHPA based chelator having the general form: ##STR4## where: "B" is a benzene ring bonded to the acetic carbon, with only the "OH" phenol radical at the ortho position, or, a benzene ring bonded to the acetic carbon, bonded with the "OH" phenol radical plus a para position phenol radical selected from the group consisting of ______________________________________ alkyl: --(CH.sub.2)--CH.sub.3, carboxyl: --COOH, nitro: --NO.sub.2, and sulfonic acid: --SO.sub.3 H; ______________________________________ and "n" is, from 2 to 4 inclusive, methyl groups within the methyl chain connecting the two Nitrogen atoms; DEPROTONATING THE EDHPA' by adding a strong base deprotonating agent for removing the protons from the four oxygen coordinate sites: ______________________________________ EDHPA Based Chelator Plus Deprotonating Agent EDHPA'(-4) - (H.sup.+).sub.4 4(Dcat.sup.+ Dan.sup.-) Yields Deprotonated EDHPA' Plus Deprotonation By-Product EDHPA'(-4) + 4Dcat.sup.+ 4(H-Dan) (EDHPA' salt) ______________________________________ where: Dan - is a deprotonating anion for pulling the protons away from the EDHPA' chelator, and Dcat + is a deprotonating cation which occupies the four negatively charged coordination points, to provide the EDHPA'(-4) ion in solution; CHELATING THE EDHPA'(-) to form EDHPA'(PM) by adding the paramagnetic metal ion in the form of a metal salt: ______________________________________ Deprotonated EDHPA' Plus Metal Salt EDHPA'(-4) + 4Dcat.sup.+ PM + 2 - 2(Can.sup.-) Yields Chelated EDHPA' Plus Chelation By-Product EDHPA'(PM).sup.-- + 2Dcat.sup.+ 2(Can-Dcat) ______________________________________ where: PM is a paramagnetic metal cation from the added metal salt, and Can - is the counter anion from the added metal salt, to provide the EDHPA based chelator in the contrast agent form of EDHPA'(PM).

Claim 38

The method of imaging a subject with a magnetic resonance (MR) imaging system employing an EDHPA based paramagnetic contrast agent EDHPA'(PM), comprising the steps of: PROVIDING a physiologically tolerable contrast agent EDHPA'(PM) having the general form: ##STR5## where: "PM" is a paramagnetic metal ion bound by chelation within the EDHPA'; "B" is a benzene ring bonded to the acetic carbon, with only the "O - " phenol radical at the ortho position, or, a benzene ring bonded to the acetic carbon, with the "O - " phenol radical plus a para position phenol radical selected from the group consisting of ______________________________________ alkyl: --(CH.sub.2)--CH.sub.3, carboxyl: --COO.sup.-, nitro: --NO.sub.2, and sulfonic acid: --SO.sub.3.sup.- ; ______________________________________ "n" is, from 2 to 4 inclusive, methyl groups within the methyl chain connecting the two Nitrogen atoms; and "IN + " is a chemically inert cation for balancing the charge the contrast agent molecule; whereby the contrast agent causes a reduction in the T1 relaxation time near the region of interest within the subject; INTRODUCING the EDHPA'(PM) contrast agent into the subject; WAITING for the phenol radicals to cooperate with the in vivo environment; and IMAGING the region of interest within a subject with the MR system to obtain a contrast agent enhanced image.

Claim 39

The method of imaging a subject with a magnetic resonance (MR) imaging system employing an EDHPA based paramagnetic contrast agent EDHPA'(PM), comprising the steps of: PROVIDING a physiologically tolerable contrast agent EDHPA'(PM) having the general form: ##STR5## where: "PM" is a paramagnetic metal ion bound by chelation within the EDHPA'; "B" is a benzene ring bonded to the acetic carbon, with only the "O - " phenol radical at the ortho position, or, a benzene ring bonded to the acetic carbon, with the "O - " phenol radical plus a para position phenol radical selected from the group consisting of ______________________________________ alkyl: --(CH.sub.2)--CH.sub.3, carboxyl: --COO.sup.-, nitro: --NO.sub.2, and sulfonic acid: --SO.sub.3.sup.- ; ______________________________________ "n" is, from 2 to 4 inclusive, methyl groups within the methyl chain connecting the two Nitrogen atoms; and "IN + " is a chemically inert cation for balancing the charge the contrast agent molecule; whereby the contrast agent causes a reduction in the T1 relaxation time near the region of interest within the subject; INTRODUCING the EDHPA'(PM) contrast agent into the subject; WAITING for the phenol radicals to cooperate with the in vivo environment; and IMAGING the region of interest within a subject with the MR system to obtain a contrast agent enhanced image.