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Details for Patent: 4,687,658

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Details for Patent: 4,687,658

Title: Metal chelates of diethylenetriaminepentaacetic acid partial esters for NMR imaging
Abstract:Homologs of Diester-DTPA-Paramagnetic compounds (such as dimethyl acetyl diethylene triamine triacetic acid) provide excellent contrast agents for magnetic resonance imaging (MRI). The magnetic dipole generated by the unpaired electron within the paramagnetic (PM) atom, causes a local reduction in the bulk magnetic field of the MRI system. The resulting shorting of the T1 (spin lattice) relaxation time in the local hydrogen protons within the area of interest, causes an intense "free induction signal" and a corresponding modulation in the collected scanning data. The tissue or organ of interest appears on the MRI display highlighted in white. Background tissue is displayed as darker or lower intensity greys. The ester homologs replace two carboxylic acids to form functional ester groups on the DTPA chelator. The homologs cause the Diester-DTPA-PM contrast agents to go into solution readily, and promotes organ selectivity.
Inventor(s): Quay; Steven C. (Menlo Park, CA)
Assignee: Salutar, Inc. (Sunnyvale, CA)
Filing Date:Oct 04, 1984
Application Number:06/657,676
Claims:1. A chemically stable physiologically tolerable contrast agent in a solid state, for use in vivo solution during diagnostic magnetic resonance imaging (MRI), to enhance the MRI image of a subject within the MRI scanning magnetic field, comprising:

a contrast agent of the form:

E-DTPA-PM,

where:

E-DTPA is an ethylene triamine pentaacetic acid chelator in which at least one of the five acetic acid groups has become a functional ester group E of the form:

E=--COO--(CH.sub.2).sub.n-1 --CH.sub.3,

wherein "n" is an integer from 1 to 16 indicating the number of Carbon atoms in the Carbon-Hydrogen portion of the ester group E,

for functionally cooperating with the in vivo environment; and

PM is a paramagnetic metal ion having an atomic charge of +Z, securely chelated at a plurality of coordination points into the E-DTPA chelator to chemically isolate the PM(+Z) ion from the in vivo environnent, for locally affecting the magnetic field of the MRI system;

whereby the contrast agent causes a reduction in the T1 relaxation time near the region of interest within the subject.

2. The contrast agent of claim 1, wherein the contrast agent is a diester of the form:

2E-DTPA-PM,

where:

2E-DTPA-PM is ethylene triamine pentaacetic acid chelator in which two of the five acetic acid groups have been become a pair of functional ester groups E of the form:

E=--COO--(CH.sub.2).sub.n-1 --CH.sub.3,

wherein n is an integer from 1 to 16 indicating the number of Carbon atoms in the Carbon-Hydrogen portion of each ester group E1 and E2.

3. The contrast agent of claim 2, wherein Z=+3 and the 2E-DTPA-PM(+3) molecule has a zero net charge.

4. The contrast agent of claim 2, wherein Z=+2 and the general form is:

2E-IN-DTPA-PM(+2),

where:

IN is an inert cation

of charge +1; and the 2E-IN-DTPA-PM(+2) molecule has a zero net charge.

5. The contrast agent of claim 1, wherein the paramagnetic metal ion PM(+Z) is at least one element selected from the group consisting of:

Cr(III)

Mn(II)

Fe(III)

Fe(II)

Co(II)

Ni(II)

Cu(III)

Cu(II)

La(III)

Ce(III)

Pr(III)

Nd(III)

Pm(III)

Sm(III)

Eu(III)

Gd(III)

Tb(III)

Dy(III)

Ho(III)

Er(III)

Tm(III)

Yb(III)

Lu(III).

6. The contrast agent of claim 1, wherein the paramagnetic metal ion PM(+Z) is at least one element selected from the group consisting of:

Cr(III)

Mn(II)

Fe(III)

Fe(II)

Gd(II)

Co(II)

Ni(II)

Cu(III)

Cu(II).

7. A chemically stable physiologically tolerable contrast agent in a pharmacological state, for in vivo use during diagnostic magnetic resonance imaging (MRI), to enhance the MRI image of a subject within the MRI scanning magnetic field, comprising:

a paramagnetic metal ion PM(+Z) having an atomic charge of Z for locally affecting the MRI scanning magnetic field within the subject to reduce the T1 relaxation time thereof;

a triamine chelator DTPA' securely polar bonded around the PM(+Z) ion at a plurality of coordination points to provide a DTPA'-PM, and having the form: ##STR9## for chemically isolating the PM(+Z) ion from the in vivo environment; functional group means formed by an ester compound of the form

--COO--(CH.sub.2).sub.n-1 --CH.sub.3,

wherein "n" is an integer indicating the number of Carbon atoms in the Carbon-Hydrogen portion of the ester compound, for functionally cooperating with the in vivo environment, covalently bonded to the DTPA'-PM chelator forming an Ester-DTPA'-PM contrast agent; and

a pharmaceutically acceptable vehicle means for dispersing the Ester-DTPA'-PM contrast agent.

8. The contrast agent of claim 7, wherein the functional group means comprises:

a first ester group having nl Carbon atoms in Carbon-Hydrogen portion, and covalently bonded to the DTPA'-PM chelator; and

a second ester group having n2 Carbon atoms in Carbon-Hydrogen portion, and covalently bonded to the DTPA'-PM chelator;

to form a Diester-DTPA'-PM.

9. The contrast agent of claim 8, wherein n1 and n2 may by any whole integer from 1 to 16.

10. The contrast agent of claim 9, wherein the Diester-DTPA'-PM is a homo-diester in which n1=n2.

11. The contrast agent of claim 9, wherein the Diester-DTPA'-PM is a hetro-diester in which n1 is larger than n2.

12. The contrast agent of claim 7, wherein the paramagnetic metal ion (PM+Z) is at leat one element selected from the group consisting of:

Cr(III)

Mn(II)

Fe(III)

Fe(II)

Co(II)

Ni(II)

Cu(III)

Cu(II)

La(III)

Ce(III)

Pr(III)

Nd(III)

Pm(III)

Sm(III)

Eu(III)

Gd(III)

Tb(III)

Dy(III)

Ho(III)

Er(III)

Tm(III)

Yb(III)

Lu(III).

13. The contrast agent of claim 7, wherein the paramagnetic metal ion (PM(+Z) is at least one element selected from the group consisting of:

Cr(III)

Mn(II)

Fe(III)

Fe(II)

Gd(II)

Co(II)

Ni(II)

Cu(III)

Cu(II).

14. The contrast agent of claim 7, wherin Z=+3 and the Ester-DTPA'-PM molecule has a zero net charge.

15. The contrast agent of claim 7, wherein Z=+2 and the further comprises an inert cation IN having an atomic charge of +1 forming a

Ester-IN(+1)-DTPA'-PM(+2) molecule with a zero net charge.

16. The contrast agent of claim 7, wherein the vehicle means is a water solution.

17. The contrast agent of claim 16, further comprising water of hydration associated with the Carbon-Hydrogen portion to the ester compound.

18. The contrast agent of claim 7, wherein the paramagnetic metal ion PM(+Z) is Fe(III).

19. The contrast agent of claim 7, wherein the paramagnetic metal ion PM(+Z) is Mn(II).

20. The contrast agent of claim 7, wherein the paramagnetic metal ion PM(+Z) is Co(II).

21. The contrast agent of claim 7, wherein the paramagnetic metal ion PM(+Z) is Gd(III).

22. The method of imaging a subject with a magnetic resonance imaging (MRI) system employing an paramagnetic contrast agent, comprising the steps of:

PROVIDING a physiologically tolerable contrast agent in the form:

2E-DTPA-PM(+Z),

where:

2E-DPTA is ethylene triamine pentaacetic acid chelator in which two of the five acetic acid groups have been become a pair of functional ester groups E of the form:

E=--COO--(CH.sub.2).sub.n-1 --CH.sub.3, wherein n is an integer from 1 to 16 indicating the number of Carbon atoms in the Carbon-Hydrogen portion of each ester group E1 and E2,

for functionally cooperating with the in vivo environment; and

PM(+Z) is a paramagnetic metal ion having an atomic charge of +Z, securely chelated at a plurality of coordination points into the 2E-DTPA chelator to chemically isolate the PM(+Z) ion from the in vivo environment, for locally affecting the magnetic field of the MRI system;

INTRODUCING the 2E-DPTA-PM contrast agent into the subject;

WAITING for the ester functional groups to cooperate with the in vivo environment; and

IMAGING the subject with the MRI system to obtain a contrast agent enhanced MRI image.

23. The method of imaging a subject as specified in claim 22, wherein the contrast agent is introduced by intravenous injection.

24. The method of imaging a subject as specified in claim 22, further comprising the initial step of dispersing the 2E-DTPA-PM contrast agent into a suitable carrier vehicle.

25. The method of imaging a subject as specified in claim 22, further comprising:

the initial step of providing data from a prior MRI imaging: and

the final step of subtraction comparing the prior MRI image with the current MRI image.

26. The method of imaging a subject as specified in claim 25, wherein the prior MRI image is a base line image.

27. The method of imaging a subject as specified in claim 25, wherein the prior MRI image is not a contrast agent enhanced image.
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