 |
Claims  |
|
|
I claim:
1. A chemically stable physiologically tolerable contrast agent in a solid
state, for use in vivo solution during diagnostic magnetic resonance (MR)
imaging, to enhance the MR image the region of interest of a subject
within the MR scanning magnetic field, comprising:
a composition of matter of the form:
A-DTPA-PM(+Z),
where:
A-DTPA is an ethylene triamine pentaacetic acid chelator in which at least
one of the five acetic acid groups has become a functional amide group A
of the form:
A=--CONH--(CH.sub.2).sub.n-1 -CH.sub.3, wherein "n" is an integer up to 16
indicating the number of Carbon atoms in the Carbon-Hydrogen portion of
the amide group A,
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 A-DTPA chelator to
chemically isolate the PM(+Z) ion from the in vivo environment, for
locally affecting the magnetic field of the MR 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 composition of matter is a
diamide of the form:
2A-DTPA-PM(+Z),
where:
2A-DTPA-PM(+Z) is ethylene triamine pentaacetic acid chelator in which two
of the five acetic acid groups have been become a pair of functional amide
groups A of the form:
A=--CONH--(CH.sub.2).sub.n-1 --CH.sub.3,
wherein n is an integer up to 16, indicating the number of Carbon atoms in
the Carbon-Hydrogen portion of each amide group.
3. The contrast agent of claim 2, wherein Z=+3 and 2A-DTPA-PM(+3) is a
molecule having a zero net charge.
4. The contrast agent of claim 2, wherein Z=+2 and the composition of
matter has the form:
2A-IN-DTPA-PM(+2),
where:
IN is an inert cation of charge +1; and
2A-IN-DTPA-PM(+2) is a molecule having a zero net charge.
5. The contrast agent of claim 1, wherein the paramagnetic metal ion PM(+Z)
within the composition of matter is at least one element selected from the
group consisting of:
______________________________________
Ions of Transition Elements
______________________________________
Cr(III) Co(II)
Mn(II) Ni(II)
Fe(III) Cu(III)
Fe(II) Cu(II)
______________________________________
______________________________________
Ions of Lanthanide Elements
______________________________________
La(III) Gd(III)
Ce(III) Tb(III)
Pr(III) Dy(III)
Nd(III) Ho(III)
Pm(III) Er(III)
Sm(III) Tm(III)
Eu(III) Yb(III)
Lu(III).
______________________________________
6. The contrast agent of claim 1, wherein the paramagnetic metal ion PM(+Z)
within the composition of matter is at least one element selected from the
group consisting of:
______________________________________
Cr(III) Co(II)
Mn(II) Ni(II)
Fe(III) Cu(III)
Fe(II) Cu(II).
Gd(II)
______________________________________
7. A chemically stable physiologically tolerable contrast agent in a
pharmacological state, for in vivo use during diagnostic magnetic
resonance (MR) imaging, to enhance the MR image of a subject within the MR
scanning magnetic field, comprising:
a paramagnetic metal ion PM(+Z) having an atomic charge of Z for locally
affecting the MR 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:
##STR5##
for chemically isolating the PM(+Z) ion from the in vivo environment;
functional group means formed by an amide compound of the form
CONH.sub.2 --(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 amide compound,
for functionally cooperating with the in vivo environment, covalently
bonded to the DTPA'-PM chelator forming an Amide-DTPA'-PM contrast agent;
and
a pharmaceutically acceptable vehicle means for dispersing the
Amide-DTPA'-PM contrast agent.
8. The contrast agent of claim 7, wherein the functional group means
comprises:
a first amide group having n1 Carbon atoms in Carbon-Hydrogen portion, and
covalently bonded to the DTPA'-PM chelator; and
a second amide group having n2 Carbon atoms in Carbon-Hydrogen portion, and
covalently bonded to the DTPA'-PM chelator;
to form a Diamide-DTPA'-PM.
9. The contrast agent of claim 8, wherein n1 and n2 may by any whole
integer from 0 to 16.
10. The contrast agent of claim 9, wherein the Diamide-DTPA'-PM is a
homo-diamide in which n1=n2.
11. The contrast agent of claim 9, wherein the Diamide-DTPA'-PM is a
hetero-diamide in which n1 is larger than n2.
12. The contrast agent of claim 7, wherein Z=+3 and the Amide-DTPA'-PM has
a zero net charge.
13. The contrast agent of claim 7, wherein Z=+2 and the further comprises
an inert cation IN having an atomic charge of +1 forming
Amide-IN(+1)-DTPA'-PM(+2) with a zero net charge.
14. The contrast agent of claim 7, wherein the vehicle means is a water
solution.
15. The contrast agent of claim 14, further comprising water of hydration
associated with the Carbon-Hydrogen portion to the amide compound.
16. The contrast agent of claim 7, wherein the paramagnetic metal ion
(PM(+Z) is at least one element selected from the group consisting of:
______________________________________
Ions of Transition Elements
______________________________________
Cr(III) Co(II)
Mn(II) Ni(II)
Fe(III) Cu(III)
Fe(II) Cu(II)
______________________________________
______________________________________
Ions of Lanthanide Elements
______________________________________
La(III) Gd(III)
Ce(III) Tb(III)
Pr(III) Dy(III)
Nd(III) Ho(III)
Pm(III) Er(III)
Sm(III) Tm(III)
Eu(III) Yb(III)
Lu(III).
______________________________________
17. 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) Co(II)
Mn(II) Ni(II)
Fe(III) Cu(III)
Fe(II) Cu(II).
Gd(II)
______________________________________
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 (MR) imaging
system employing an paramagnetic contrast agent, comprising the steps of:
Providing a physiologically tolerable contrast agent in the form:
2A-DTPA-PM(+Z),
where:
2A-DTPA is ethylene triamine pentaacetic acid chelator in which two of the
five acetic acid groups have been become a pair of functional amide groups
A of the form:
A=--CONH--(CH.sub.2).sub.n-1 --CH.sub.3, wherein n is an integer up to 16,
indicating the number of Carbon atoms in the Carbon-Hydrogen portion of
each amide group,
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 2A-DTPA chelator
to chemically isolate the PM(+Z) ion from the in vivo environment, for
locally affecting the magnetic field of the MR system;
introducing the 2A-DTPA-PM contrast agent into the subject;
Waiting for the amide functional groups 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 MR 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 2A-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 MR imaging: and
the final step of subtraction comparing the prior MR image with the current
MR image.
26. The method of imaging a subject as specified in claim 22, wherein the
region of interest is the gall bladder and the colon.
27. The method of imaging a subject as specified in claim 26, wherein the
resulting image is a perspective image of the surface of the colon. |
|
 |
|
 |
Claims |
|
|
|
Description |
|
|
TECHNICAL FIELD
This invention relates to MR contrast agents, and more particularly to
homologs of Amide DTPA-PM contrast agents.
BACKGROUND
Schering (German Pat. No. 3,129,906) by Gries, Rosenberg, and Weinstien
teaches the incorporation of paramagnetic metals into diethylene triamine
pentaacetic acid (DTPA) forming chelates useful as a contrast agent in
magnetic resonance imaging. The contrast agent DTPA-(GdIII) as taught by
Schering is insoluble in water and requires the addition of cations "C+"
(amines such as glucamine, N-methylglucamine, etc.) as shown below: The
charge balance of the Schering DTPA-Gd(III) ion is:
______________________________________
Schering DTPA-Gd(III) Charge Balance
______________________________________
C+ C+ DTPA Gd
+1 +1 -5 +3 = 0
______________________________________
The resulting contrast agent has three ion particles in solution for each
paramagnetic atom (a particle to PM ratio of 3:1). A paramagnetic metal
with a valence of two, such as Mn, would require an additional glucamine
ion:
______________________________________
Schering DTPA-Mn(II) Charge Balance
______________________________________
C+ C+ C+ DTPA Mn
+1 + +1 +1 -5 +3 = 0
______________________________________
raising the PM to particle ratio to 4:1.
These contrast agents raise the in vivo ion concentration and disturb the
local osmolarity balance. The osmolarity is normally regulated at about
300 milliosmols per liter. Increasing the osmolarity with injected ions,
causes water to collect within the unbalance region which dilutes the ion
concentration.
SUMMARY
It is therefore an object of this invention to provide improved amide
contrast agents for MR imaging.
It is another object of this invention to provide MR amide contrast agents
which have a high stability, a low toxicity and is physiologically
tolerable.
It is a further object of this invention to provide amide contrast agents
in pharmacological form with a low osmolarity.
It is a further object of this invention to provide amide contrast agents
which are in vivo responsive.
It is a further object of this invention to provide amide contrast agents
which are organ selective.
It is a further object of this invention to provide amide contrast agents
which cause surface highlighting of the small and large intestine.
It is a further object of this invention to provide a method of
manufacturing such amide contrast agents.
It is a further object of this invention to provide a method of using such
amide contrast agents.
It is a further object of this invention to provide an MR system employing
such amide contrast agents.
Briefly, these and other objects of the present invention are accomplished
by providing a chemically stable physiologically tolerable contrast agent
in a pharmacological state, for in vivo use during diagnostic magnetic
resonance (MR) imaging. The contrast agent enhances the MR image of a
subject within the MR scanning magnetic field. A paramagnetic metal ion
PM(+Z) having an atomic charge of Z locally affects the MR scanning
magnetic field to reduce the T1 relaxation time of local protons within
the subject. The contrast agent contains a triamine chelator DTPA'
securely polar bonded around the PM(+Z) ion at a plurality of coordination
points, and has the form:
##STR1##
for chemically isolating the PM(+Z) ion from the in vivo environment. The
contrast agent also contains a functional amide group of the form:
##STR2##
wherein "n" is an integer from 0 to 16 indicating the number of Carbon
atoms in the Carbon-Hydrogen portion of each amide group. The functional
amide may be a homo-diamide or a hetero-diamide. The Amide-DTPA'-PM
contrast agent is dispensed in a pharmaceutically acceptable vehicle means
such as water. The Carbon-Hydrogen portion to the amide compound becomes
associated with water of hydration which increases the paramagnetic
strength of the contrast agent. The PM ion may have a valence of +3 and
produce a contrast agent molecule of zero net charge. The PM ion may have
a valence of +2 and require an inert cation IN having an atomic charge to
produce a molecule with a zero net charge. The paramagnetic metal ion
PM(+Z) is at least one element selected from the Transition Elements 24-29
or the Lanthanide Elements 57-71.
BRIEF DESCRIPTION OF THE DRAWING
Further objects and advantages of the present paramagnetic contrast agents,
and the method of manufacture and use thereof, will become apparent from
the following detailed description and drawing in which:
FIG. 1A is a diagram showing the chelate structure and water of hydration
of a Diamide-DTPA-PM(Z) contrast agent in which Z=+3;
FIG. 1B is a diagram showing the chemical structure of the Diamide-DTPA-PM
contrast agent of FIG. 1A;
FIG. 1C is a diagram showing the chemical structure of a general
Diamide-DTPA-PM(Z) contrast agent in which Z=+2;
FIG. 2 is a diagram showing the anhydride ammonium hydroxide production of
Dimethyl-DTPA-PM(Z) in which Z=+3;
FIG. 3 is a diagram showing the anhydride butyl amine production of
Dibutyl-DTPA-PM(Z) in which Z=+2;
FIG. 4A is a colon shown in cross section;
FIG. 4B is a planar schematic drawing of an MR image of a colon showing
surface highlighting by Diamide-DTPA-PM;
FIG. 4C is a perspective schematic drawing of an MR image of a colon
showing surface highlighting by Diamide-DTPA-PM of occulted and
non-occulted surfaces;
FIG. 5 is a cut-away perspective view of an MR system showing the motion
platform and subject using Diamide-DTPA-PM paramagnetic contrast agents;
and
FIG. 6 is a flow chart showing a method of using the Diamide-DTPA-PM
paramagnetic contrast agents.
DIAMINE-DTPA-PM CONTRAST AGENTS (FIG. 1A 1B 1C)
The present paramagnetic contrast agents are amide homologs of the DTPA-PM
chelate, having the general chemical name diamido acetyl-diethylene
triamine triacetic acid (or Diamide-DTPA). The probable physical chelation
structure of Diamide-DTPA-PM is a classic octahedron (8 faces, 6 apexes)
as shown in FIG. 1A. The Diamide-DTPA homologs are strong chelators having
six polar bond coordination points 104 (three nitrogen points 104:N and
three oxygen points 104:O) which enclose the paramagnetic ion PM(Z) on all
sides.
Diamide-DTPA-PM has the general chemical structure shown in FIG. 1B. The
homologs thereof have similar structures with a specific number "n" of
carbons in the Carbon-Hydrogen portion of the amide group. The number of
Carbons in the methylene CH2 chain between the --CONH-- active group and
the terminal methylene --CH3, is "n-1".
Two of the original five DTPA acetic acid groups have become amide groups
"A". In general:
Diamide-DTPA-PM=2A-DTPA'-PM
where A is a general amide group of the form:
##STR3##
and DTPA' is a modification of Schering DTPA of the form:
##STR4##
and PM is a paramagnetic metal ion. The elimination of the two acetic acid
groups reduces the ion charge of the DTPA chelator from five to three.
Paramagnetic ions having a valence of Z=+3 as shown in FIG. 1A and 1B,
produce a diamide contrast agent of the general form:
Diamide-DTPA-PM(+3)=2A-DTPA'-PM(+3).
This Type III contrast agent has a zero net charge as tabulated below:
______________________________________
Diamide-DTPA-PM(+3) Charge Balance
______________________________________
2A DTPA' PM
(+0) + (-3) + (+3) = 0.
______________________________________
The particle (osmolarity) to paramagnetic (molar relaxivity) ratio for
Diamide-DTPA-PM(+3) type contrast agents (Z=+3) is 1:1. The
Diamide-DTPA-PM(Z) contrast agents formed around plus III paramagnetic
metals can be prepared in highly concentrated solutions while retaining
isotonicity with body fluids. The Schering DTPA-PM(+3) has a particle to
paramagnetic ratio of 3:1, and can only be made in isotonic solutions at
substantially lower concentrations. Therefore, greater volumes of the
Schering DTPA-PM(+3) need be injected into animals or humans to obtain the
same paramagnetic effect.
Paramagnetic ions having a valence of Z=2, produce amide contrast agents of
the general form:
Diamide-IN-DTPA-PM(+2)=2A-IN-DTPA'-PM(+2)
where IN is a suitable inert ion, such as a simple mineral salt cation
(Na+, Li+, etc,) or an organic ion such as Methyl glucamine or N-methyl
glucamine, having a charge of plus one (see FIG. 1C). This Type II
contrast agent also has a zero net charge as tabulated below:
______________________________________
Diamide IN-DTPA-PM(+2) Charge Balance
______________________________________
2A IN DTPA' PM
(+0) + (+1) + (-3) + (+3) = 0.
______________________________________
The particle to paramagnetic ratio for the IN-Diamide-DTPA-PM(+2) contrast
agents is 2:1, producing a low osmolarity impact.
The above Diamide-DTPA-PM Type III and Type II contrast agents have a
paramagnetic effect similar to the Schering DTPA-PM. For example, Methyl
Amide DTPA-Gd(III) requires a concentration of about 3.31 mM to produce a
T1 relaxation time of 67 nsec (10 MHz field strength, using an RADX). The
concentration of Schering DTPA-Gd(III) required to produce a similar
result is about 3.16. Methyl Amide DTPA-Gd(III) has about the same
paramagnetism of Schering DTPA-Gd(III).
Possibly the water of hydration 108 (see FIG. 1A) which collects around the
amide CH2 chains offers a reliable source of protons (H+) 110 for
resonanting with the applied MR fields. Protons 110 have a high
probability of being present within the local magnetic filed of the PM
ions. These protons form a class of protons for MR imaging which is
distinct from random in vivo protons. The prolonged association time of
bound water 108, and the close proximity of protons 110 to the PM ion,
establishes a definite and distinct T1 relaxation time which is longer
than the T1 for random protons. As a result, protons 110 provided by the
water of hydration appear at a higher intensity in the MR image.
METHOD OF MANUFACTURE (FIGS. 2 and 3)
A general anhydride-diamide method is suitable for making each homolog of
the amide family of DTPA'-PM contrast agents. In the example below the
paramagnetic ion is provided by Fe(III)-(Cl)3, for chelation into dimethyl
amide (n=1). However, other paramagnetic ions in other forms may be
employed for chelation into other amide homologs.
Step (1)
Formation of Amide-DTPA (see FIG. 2)
Mix 1-5 grams dianhydride DTPA (obtained from Signma Chemical Co, St Louis
MO.) into 50-150 mL of 5 percent (v/v) NH4-OH (ammonium hydroxide) in
water. Fixed ratios of NaOH/DTPA are not required, Precise so long as
excess NH4OH is provided.
Step (2)
Heat the solution for several hours (overnight) at reflux temperature, to
produce the amide derivative Dimethyl-DTPA (n=1) plus water.
Higher homologs of Diamide-DTPA may be formed using the corresponding
higher homolog of alkyl amines for the reactant. Chloroform may be used as
the solvent for higher homologs.
Formation of the Dibutyl-DTPA (n=4) diamide homolog is shown in FIG. 3.
Step (3)
Remove the excess solvent, by vacuum rotary evaporation leaving an
Diamide-DTPA crystal residue.
Step (4)
Mix the Diamide-DTPA residue in an FeC13 water solution of stoichiometric
proportions, to form Diamide-DTPA-(Fe+3) plus 3HC1.
Type II metals will require an inert cation (IN) which may be added to the
solution at this point.
Step (5)
Remove the HC1
(A) by evaporation using a rotary evaporator.
(B) by neutralization using NaOH or NH40H.
(C) by chromatograpy using a silica gel column.
Step (6)
Remove the water by vacuum-freezing to form a highly stable form of
Diamide-DTPA-PM.
Step (7)
Disperse the Amide-DTPA-PM in suitable vehicle to provide a pharmacological
form.
Water is a suitable vehicle for dissolving the lower homologs of
Diamide-DTPA-PM (n less than 10). Higher homologs are hydrophobic and form
an emulsion with water. These higher homologs have the same density as
water and therefore do not settle out. The isodense character of the
homologs of Diamide-DTPA-PM permits a wide range of water:homolog ratios.
ESTER FAMILY (n=0 to n=16)
The amide family of DTPA'-PM contrast agents include the homo-diamides
(n=n') structures and the hetero-diamides (n not equal to n') structure.
______________________________________
Name of Amide n,n' Properties of Interest
______________________________________
Diamide-DTPA-PM
0,0 Excellent
Methyl-DTPA-PM
1,1 renal and
Ethyl-DTPA-PM 2,2 blood-brain
Propyl-DTPA-PM
3,3 barrier contrast
Butyl-DTPA-PM 4,4 agent.
Pentyl-DTPA-PM
5,5 Demonstrates renal
Hexyl-DTPA-PM 6,6 and hepatobiliary
Heptyl-DTPA-PM
7,7 imaging.
Octyl-DTPA-PM 8,8 Also shows cardiac
Nonyl-DTPA-PM 9,9 imaging of infarctions
Decyl-DTPA-PM 10,10 and ischemic lesions.
to 16,16
Diamide-Stearyl-
0,16 Passes into the
DTPA-PM Cardiac system imaging.
______________________________________
The hetero-diamides have one short CH2 chain (n=1 or more), and one long
CH2 chain (n=16 or less). A single long hydrophobic chain, together with
the charged DTPA' moiety, renders the chelate an isosteric substitute for
fatty acids; and produces substantial tissue levels of the chelate in
those organs which have efficient fatty acid uptake systems such as the
myocardium.
ORGAN SELECTIVE (FIG. 4A 4B 4C)
Venously introduced contrast agents are immediately distributed throughout
the circulatory system for imaging. Organs such as the kidney, brain,
liver, and heart receive substantial blood flow; and provide selective
images which are agent enhanced.
Amide-DTPA-PM has a prolonged circulation time due to its high stability.
The Amide contrast agent is less affected by ensymes degradation than
simple ion-DTPA chelates (Schering). In addition, the higher homologs of
Amide-DTPA-PM tend to be less polar and to bind more to serum proteins,
further increasing their circulation time. They tend to be extracted from
circulation by the liver and excreted in the hepatobiliary system. The
amide contrast agent passes through the bile duct (controlled by the
ampulla of Vater) and is absorbed into the colon. The Amide contrast
agents are suitable for imaging the hepatobiliary (gall bladder) system.
FIG. 4A is a cross sectional view of the colon 440. The diamide appearing
along the convoluted inner surface of the colon wall 442 is slowly brushed
away by the luminal content 444. The high viscosity of the contrast agent
prevents it from immediately mixing with the luminal content 444. Because
the washout rate is slower than the excretion rate, the agent accumulates
in a film or layer 446 along the inner surface of colon 440.
The paramagnetic properties of amide enriched layer 446 establishes a
shorter T1 relaxation time for the local Protons within the layer. In the
resulting MR image, amide layer 446 is displayed at a higher intensity,
highlighting the inner surface of the colon 440. Surface highlighted
images are particularly useful in studying those disease processes
involving changes in mucosal transit such as malabsorption, non-tropical
sprue, ulceratine colitis, regional enteritis etc. The luminal content is
not amide enriched and appears grey or dark (unenhanced) along with the
background tissue.
FIG. 4B shows a schematic MR image of the colon in cross-section, and FIG.
4C shows a schematic MR image of the colon in perspective. Both simple
planar views and the complex perspective views can be computer generated
from the MR data. The surface amide accumulation 446 appears bright and
outlines of the inner surface colon 440 unimpedded by the luminal content.
This surface effect is especially noticeable in persepctive view 4C which
reveals the front surface 448-F, and both the unocculted back surface
448-B and occulted back surface 448-O. The thin amide layer 446 on the
front surface has a transparent characteristic which permits the occulted
back surface to be viewed. The display intensity of the region of overlap
between the front surface 448-F and occulted back surface 448-O is the
summation of the separate intensities.
The lower homologs tend to be more polar and remain in solution longer.
These homologs are kidney selective and suitable for imaging the kidney,
ureter, and bladder.
The higher homologs are fatty acid analogs and are thus extracted by the
heart along with the regular fatty acids. These homologs (n=7 and greater)
are cardiac selective and suitable for imaging the cardiac system and
cardiac related functions.
Oral introduction of the Diamide-DTPA-PM contrast agent requires a higher
volume. The agent fills the luminal channel of the digestive system for
providing a volume or bulk MR image.
STABLE-POWDER STATE
The stable powder state of the Diamide-DTPA-PM contrast agents have an
indefinite shelf life, and is the preferred state for shipping and
storage. The contrast agent in water solution (or other solvent) is
packaged in small storage vials, and frozen under a vacuum. The low
pressure sublimates the solvent, leaving crystals of the contrast agent.
The vial is sealed to prevent entry of external contaminants, and to to
preserve the internal vacuum. The resulting freeze-dried, vacuum sealed
powder, is highly stable and free from environmental degradation effects.
PHARMACOLOGICAL-SOLUTION STATE
Prior to injection, the stable-powdered contrast agent may be raised to the
pharmacological state by the addition of a suitable solvent such as water,
serum, albumin solutions, or saline. A typical injectable composition
contains about 10 mg human serum albumin (1 percent USP Parke-Davis) and
from about 10 to 500 micrograms of Diamide-DTPA-PM material per milliliter
of 0.01M phosphate buffer (pH 7.5) containing 0.9 percent NaCl. The pH of
the aqueous solutions may range between 5-9, preferably between 6-8. The
storage vial may have twin compartments containing the desired amounts of
powdered Diamide-DTPA-PM and solvent for a single application. When the
seal between the compartments is broken, the Diamide-DTPA-PM goes into
solution at the desired concentration for immediate use. The
Diamide-DTPA-PM solution mixes readily with the in vivo fluids.
PARMAGNETIC EXAMPLES
Paramagnetic material PM may be any paramagnetic element, molecule, ion or
compound having a combined valance of "Z". paramagnetic material PM
includes at least one of the following elements:
______________________________________
Ions of Transition Elements
______________________________________
Cr(III) 24 (Chromium) Co(II) 27 (Cobalt)
Mn(II) 25 (Manganese) Ni(II) 28 (Nickel)
Fe(III) 26 (Iron) Cu(III)
29 (Copper)
Fe(II) 26 (Iron) Cu(II) 29 (Copper)
______________________________________
______________________________________
Ions of Lanthanide Elements
______________________________________
La(III)
57 (Lanthanum) Gd(III)
64 (Gadolinium)
Ce(III)
58 (Cerium) Tb(III)
65 (Terbium)
Pr(III)
59 (Praseodymium)
Dy(III)
66 (Dysprosium)
Nd(III)
60 (Neodymium) Ho(III)
67 (Holmium)
Pm(III)
61 (Promethium) Er(III)
68 (Erbium)
Sm(III)
62 (Samarium) Tm(III)
69 (Thulium)
Eu(III)
63 (Europium) Yb(III)
70 (Ytterbium)
Lu(III)
71 (Lutetium)
______________________________________
Gd has the highest paramagnetic property; but is a costly and highly toxic
in the free state. Placing the Gd within the chelator produces a
physiologically tolerable form of Gd; but also reduces paramagnetic effect
of the Gd. The chelate structure tends to shield the paramagnetic ions and
prevents close proximity to local H+ protons. Fe and Mn have a high
paramagnetic property and excellent physiological tolerance. Both of these
paramagnetic ions are normally present in the physiological environment.
GENERAL MR SYSTEM (FIG. 5)
Magnetic resonance (MR) imaging system 500 has two magnetic components
which scan subject 504 for obtaining MR data enhanced by the presence of
contrast agent 508. Bulk magnetic filed Mz from Z field source 510 causes
paramagnetic particles such as local hydrogen protons within the subject
to aline with the Z axis. Periodic or rotating field Mxy from XY field
generator 514 extends between XY electrodes 516. The subject to be scanned
is positioned on support platform 520 and moved through the magnetic
fields by drive 522. Rotating field Mxy is tuned to cause resonant
precession of the local protons within the tissue of interest. Each local
proton precesses about the Z axis in response to a particular frequency of
rotating field Mxy. When rotating field Mxy is removed, the precessing
protons decay back into alinement with Mz.
The decay period of the local protons (spin lattice relaxation time T1)
varies between organs and between conditions within the same organ. Tumor
tissue tends to have a longer T1 than healthy tissue. The presence of the
paramagnetic metal ions PM causes a shortening of the proton T1, without
substantially affecting T2 (spin-spin relaxation time). The energy of
precession is released forming a free induction signal. Grid detector 526
senses the decay signals which are stored and processed by data processer
system 530. to form an image 532 on monitor 536. The metal ion in the
contrast agent are not directly imaged by the MR system.
The imaging system if further disclosed in Scientific American, May 1982,
pages 78-88, and "NMR A Primer for Medical Imaging" by Wolf and Popp Slack
Book Division (ISBN 0-943432-19-7), which disclosures are hereby
incorporated by reference.
METHOD OF USE (FIG. 6)
FIG. 6 shows a method of imaging subject 504 with MR system 500 employing
an paramagnetic contrast agent 508.
Step (1)
Providing a physiologically tolerable contrast agent 508 in the form:
2A-DTPA-PM(+Z).
If initially in powder form, the 2A-DTPA-PM contrast agent must be
dispensed into a suitable carrier vehicle.
Step (2)
Introducing the 2A-DTPA-PM contrast agent into subject 508 (preferably by
intravenous injection).
Step (3)
Waiting for the amide functional groups to cooperate with the in vivo
environment.
Step (4)
Imaging the subject with MR system 500 to obtain an enhanced MR image.
Comparison or subtraction imaging, requires an initial step of providing
data from a prior MR imaging, and the final step of subtraction comparing
the prior MR image with the current MR image. A historical base line image
from the subjects file may be employed as the prior image. Alternatively,
a current MR image made without the use of a contrast agent may be
employed.
INDUSTRIAL APPLICABILITY
It will be apparent to those skilled in the art that the objects of this
invention have been achieved as described hereinbefore by providing an
improved physiologically tolerable contrast agents with a high stability,
and a low toxicity. The contrast agent has a high paramagnetic effect due
to the amide water of hydration, and a low osmolarity due to the amide
bonding. The variability of the amide structure permits a range of vivo
response and organ selection, including surface selectivity of the colon.
CONCLUSION
Clearly various changes may be made in the structure and embodiments shown
herein without departing from the concept of the invention. Further, the
features of the embodiments shown in the various Figures may be employed
with the embodiments of the other Figures.
Therefore, the scope of the invention is to be determined by the
terminology of the following claims and the legal equivalents thereof.
* * * * *
|
|
|
|
|
|
|
Description |
|
