# US 7,412,279 B2 · Systems and methods for targeted magnetic resonance imaging of the vascular system

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- Number: US 7,412,279 B2
- Document ID: US7412279B2
- Status: Granted
- Kind: B2
- Application number: 10/209,416
- Filed: 2002-07-30
- Published: 2003-02-06
- Granted: 2008-08-12
- Earliest claimed: 2001-07-30
- Assignees: Epix Pharmaceuticals, Inc.
- Inventors: Robert M. Weisskoff; Peter D. Caravan; Sonia Witte; Randall B. Lauffer; Alan P. Carpenter, Jr.
- Web page: https://patentgrep.com/patent/US7412279B2

## CPC

- A61B 5/416: {the spleen}
- A61B 5/055: involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)

## Abstract

This invention relates to MRI-based methods and systems useful for diagnosing and clinically assessing the presence, location, and size of cardiovascular disease-associated stationary targets, e.g., thrombi and atherosclerotic lesions, within the vascular system. Methods and systems of the invention allow for improved anatomical information to be obtained from MRI images and allow the clinician to develop more effective treatment plans. In one aspect, the invention provides a method of determining the presence or absence of a stationary target within the vascular system of a mammal wherein two MRI data sets representing images of the vascular system and the stationary target are acquired after administration of a targeted MRI contrast agent. In another embodiment, both a targeted MRI contrast agent and a vascular MRI contrast agent are administered to a mammal, and both a vascular MRI and a targeted MRI data set are acquired.

## Claims

### Claim 1

A method of determining the presence or absence of a thrombus, an atherosclerotic plaque, an atherosclerotic lesion, a tumor, or a thromboembolism within a vascular system of a mammal comprising:
a) administering a targeted MRI contrast agent to the mammal, the targeted MRI contrast agent having a specific affinity for the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, and the targeted MRI contrast agent further capable of providing contrast enhancement of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism and the vascular system of the mammal;
b) acquiring a first MRI data set comprising an image of the vascular system; and
c) acquiring a second MRI data set, the second MRI data set acquired at a time appropriate to provide an observable level of contrast enhancement of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, if present, relative to background blood and tissue enhancement;
wherein the targeted MRI contrast agent is selected from the group consisting of:

### Claim 2 (depends on 1)

The method according to claim 1, further comprising comparing the first and second MRI data sets to determine the presence of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism within the vascular system, provided that the second MRI data set indicates the presence of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the comparing step comprises combining the first and second MRI data sets to produce a third MRI data set, the third MRI data set comprising an image of both the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism and the vascular system, and the third data set capable of indicating the location of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, if present, within the vascular system.

### Claim 4 (depends on 3)

The method according to claim 3, further comprising displaying the third MRI data set on a display device in order to indicate the location of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, if present, within the vascular system.

### Claim 5 (depends on 3)

The method according to claim 3, wherein the third MRI data set is further capable of indicating the size of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism within the vascular system.

### Claim 6 (depends on 3)

The method according to claim 3, wherein the combining step comprises registering spatially the first and second MRI data sets with respect to one another.

### Claim 7 (depends on 3)

The method according to claim 3, wherein the combining step further comprises interpolating the spatial resolution of either the first or the second MRI data set so that the first and second MRI data set are of equivalent spatial resolution.

### Claim 8 (depends on 7)

The method according to claim 7, wherein said interpolating step comprises:
determining which of the first and second data sets has the higher spatial resolution;
and
interpolating the spatial resolution of the corresponding other data set to the data set determined to have the higher spatial resolution.

### Claim 9 (depends on 7)

The method according to claim 7, wherein said combining step further comprises a direct calculation of modified image intensities resulting from a combination of individual values from registered, interpolated data elements from the first and second data sets.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the direct calculation of modified image intensities includes variably weighting the individual values of the registered, interpolated data elements from the first and second data sets.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the targeted MRI contrast agent is administered at a dose sufficient to result in a blood T1 after administration of less than 500 ms.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the targeted MRI contrast agent is administered at a dose sufficient to result in a blood T1 after administration of less than 300 ms.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the targeted MRI contrast agent is administered at a dose sufficient to result in a blood T1 after administration of less than 175 ms.

### Claim 14 (depends on 1)

The method according to claim 1, wherein the targeted MRI contrast agent further exhibits a specific affinity for a non-stationary biological component present within the mammal's vascular system.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the non-stationary biological component present within the mammal's vascular system is selected from the group consisting of human serum albumin, fibrinogen, alpha acid glycoprotein, globulins, and lipoproteins.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the non-stationary biological component present within the mammal's vascular system is human serum albumin.

### Claim 17 (depends on 1)

The method according to claim 1, wherein the targeted MRI contrast agent is administered at a dose sufficient to result in a T1 of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism of less than 500 ms.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the targeted MRI contrast agent is administered at a dose sufficient to result in a T1 of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism of less than 300 ms.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the targeted MRI contrast agent is administered at a dose sufficient to result in a T1 of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism of less than 100 ms.

### Claim 20 (depends on 1)

The method according to claim 1, wherein the targeted MRI contrast agent is administered at a dose from about 0.001 to about 500 μmol/kg.

### Claim 21 (depends on 20)

The method according to claim 20, wherein the dose is from about 0.001 to about 50 μmol/kg.

### Claim 22 (depends on 21)

The method according to claim 21, wherein the dose is from about 0.001. to about 5 μmol/kg.

### Claim 23 (depends on 1)

The method according to claim 1, wherein the targeted MRI contrast agent's specific affinity for the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, expressed as a dissociation constant, is less than 50 μM.

### Claim 24 (depends on 23)

The method according to claim 23, wherein the targeted MRI contrast agent's specific affinity for the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, expressed as a dissociation constant, is less than 5 μM.

### Claim 25 (depends on 24)

The method according to claim 24, wherein the targeted MRI contrast agent's specific affinity for the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, expressed as a dissociation constant, is less than 0.5 μM.

### Claim 26 (depends on 1)

The method according to claim 1, wherein the second MRI data set is acquired using a spoiled gradient echo sequence.

### Claim 27 (depends on 1)

The method according to claim 1, wherein the first and second MRI data sets are acquired in a single MRI session.

### Claim 28 (depends on 27)

The method according to claim 27, wherein the single MRI session lasts for less than 6 hours.

### Claim 29 (depends on 28)

The method according to claim 28, wherein the single MRI session lasts for less than 4 hours.

### Claim 30 (depends on 29)

The method according to claim 29, wherein the single MRI session lasts for less than 2 hours.

### Claim 31 (depends on 30)

The method according to claim 30, wherein the single MRI session lasts for less than 1 hour.

### Claim 32

A method of determining the presence or absence of a thrombus, an atherosclerotic plaque, an atherosclerotic lesion, a tumor, or a thromboembolism within a vascular system of a mammal comprising:
a) administering a targeted MRI contrast agent to the mammal, the targeted contrast agent having a specific affinity for the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism and the targeted contrast agent capable of providing contrast enhancement of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism;
b) administering a vascular MRI contrast agent to the mammal, the vascular contrast agent capable of providing contrast enhancement of the vascular system of the mammal;
c) acquiring a vascular MRI data set comprising an image of the vascular system; and
d) acquiring a targeted MRI data set, the targeted data set acquired at a time appropriate to provide an observable level of contrast enhancement of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, if present, relative to background blood and tissue enhancement;
wherein the targeted MRI contrast agent is selected from the group consisting of:

### Claim 33 (depends on 32)

The method according to claim 32, further comprising comparing the vascular and targeted MRI data sets to determine the presence of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism within the vascular system, provided that the targeted MRI data set indicates the presence of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism.

### Claim 34 (depends on 33)

The method according to claim 33, wherein the comparing step comprises combining the vascular and targeted MRI data sets to produce a third MRI data set, the third data set comprising an image of both the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism and the vascular system, and the third data set capable of indicating the location of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, if present, within the vascular system.

### Claim 35 (depends on 34)

The method according to claim 34, further comprising displaying the third MRI data set on a display device in order to indicate the location of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, if present, within the vascular system.

### Claim 36 (depends on 34)

The method according to claim 34, wherein the third MRI data set is further capable of indicating the size of the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism within the vascular system.

### Claim 37 (depends on 34)

The method according to claim 34, wherein the combining step comprises registering spatially the targeted and vascular MRI data sets with respect to one another.

### Claim 38 (depends on 34)

The method according to claim 34, wherein the combining step further comprises interpolating the spatial resolution of either the vascular or the targeted MRI data set so that the vascular and targeted MRI data sets are of equivalent spatial resolution.

### Claim 39 (depends on 38)

The method according to claim 38, wherein the interpolating step comprises:
determining which of the vascular or targeted MRI data sets has the higher spatial resolution; and
interpolating the spatial resolution of the corresponding other data set to the data set determined to have the higher spatial resolution.

### Claim 40 (depends on 38)

The method according to claim 38, wherein the combining step further comprises a direct calculation of modified image intensities resulting from a combination of individual values from registered, interpolated data elements from the vascular and targeted MRI data sets.

### Claim 41 (depends on 40)

The method according to claim 40, wherein the direct calculation of modified image intensities includes variably weighting the individual values of the registered, interpolated data elements from the vascular and targeted MRI data sets.

### Claim 42 (depends on 32)

The method according to claim 32, wherein the targeted contrast agent is administered prior to the vascular contrast agent, and wherein the vascular MRI data set is acquired prior to the targeted MRI data set.

### Claim 43 (depends on 32)

The method according to claim 32, wherein the targeted contrast agent and the vascular contrast agent are administered simultaneously, and wherein the targeted MRI data set is acquired prior to the vascular MRI data set.

### Claim 44 (depends on 32)

The method according to claim 32, wherein the targeted contrast agent and the vascular contrast agent are administered within 2 hours of one another.

### Claim 45 (depends on 44)

The method according to claim 44, wherein the targeted contrast agent and the vascular contrast agent are administered within 30 min. of one another.

### Claim 46 (depends on 45)

The method according to claim 45, wherein the targeted contrast agent and the vascular contrast agent are administered within 15 min. of one another.

### Claim 47 (depends on 32)

The method according to claim 32, wherein the targeted MRI data set and the vascular MRI data set are acquired in a single MRI session.

### Claim 48 (depends on 32)

The method according to claim 32, wherein the vascular MRI contrast agent is administered at a dose sufficient to result in a blood T1 after administration of less than 300 ms.

### Claim 49 (depends on 48)

The method according to claim 48, wherein the vascular MRI contrast agent is administered at a dose sufficient to result in a blood T1 after administration of less than 175 ms.

### Claim 50 (depends on 48)

The method according to claim 48, wherein the vascular MRI contrast agent is administered at a dose sufficient to result in a blood T1 after administration of less than 100 ms.

### Claim 51 (depends on 32)

The method according to claim 32, wherein the vascular MRI contrast agent is an extracellular MRI contrast agent selected from the group consisting of:

### Claim 52 (depends on 32)

The method according to claim 32, wherein the vascular MRI contrast agent is selected from the group consisting of ultra-small particles of iron oxide (USPIOs) and monocrystalline iron oxide particles (MIONs).

### Claim 53 (depends on 32)

The method according to claim 32, wherein the vascular MRI contrast agent is a blood pool contrast agent.

### Claim 54 (depends on 53)

The method according to claim 53, wherein the vascular MRI blood pool contrast agent is selected from the group consisting of:

### Claim 55 (depends on 32)

The method according to claim 32, wherein the vascular MRI contrast agent further exhibits a specific affinity for a non-stationary biological component present within the mammal's vascular system.

### Claim 56 (depends on 55)

The method according to claim 55, wherein the non-stationary biological component present within the mammal's vascular system is selected from the group consisting of human serum albumin, fibrinogen, alpha acid glycoprotein, globulins, and lipoproteins.

### Claim 57 (depends on 56)

The method according to claim 56, wherein the non-stationary biological component present within the mammal's vascular system is human serum albumin.

### Claim 58 (depends on 32)

The method according to claim 32, wherein the targeted MRI contrast agent is administered at a dose sufficient to result in a T1 of the stationary target of less than 500 ms.

### Claim 59 (depends on 58)

The method according to claim 58, wherein the targeted MRI contrast agent is administered at a dose sufficient to result in a T1 of the stationary target of less than 300 ms.

### Claim 60 (depends on 59)

The method according to claim 59, wherein the targeted MRI contrast agent is administered at a dose sufficient to result in a T1 of the stationary target of less than 100 ms.

### Claim 61 (depends on 32)

The method according to claim 32, wherein the targeted MRI contrast agent is administered at a dose from about 0.001 to about 500 μmol/kg and the vascular MRI contrast agent is administered at a dose from about 0.01 to about 300 μmol/kg.

### Claim 62 (depends on 61)

The method according to claim 61, wherein the targeted MRI contrast agent is administered at a dose from about 0.001 to about 50 μmol/kg and the vascular MRI contrast agent is administered at a dose from about 0.01 to about 30 μmol/kg.

### Claim 63 (depends on 62)

The method according to claim 62, wherein the targeted MRI contrast agent is administered at a dose from about 0.001 to about 5 μmol/kg and the vascular MRI contrast agent is administered at a dose from about 0.01 to about 3 μmol/kg.

### Claim 64 (depends on 32)

The method according to claim 32, wherein the targeted MRI contrast agent's specific affinity for the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, expressed as a dissociation constant, is less than 50 μM.

### Claim 65 (depends on 64)

The method according to claim 64, wherein the targeted MRI contrast agent's specific affinity for the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, expressed as a dissociation constant, is less than 5 μM.

### Claim 66 (depends on 65)

The method according to claim 65, wherein the targeted MRI contrast agent's specific affinity for the thrombus, the atherosclerotic plaque, the atherosclerotic lesion, the tumor, or the thromboembolism, expressed as a dissociation constant, is less than 0.5 μM.

### Claim 67 (depends on 32)

The method according to claim 32, wherein the targeted MRI data set is acquired using a spoiled gradient echo sequence.

### Claim 68 (depends on 32)

The method according to claim 32, wherein the vascular MRI contrast agent is administered as a bolus.

### Claim 69 (depends on 32)

The method according to claim 32, wherein the vascular MRI contrast agent is administered by infusion, with an infusion time of less than 15 minutes.

### Claim 70 (depends on 69)

The method according to claim 69, wherein the infusion time is less than 10 minutes.

### Claim 71 (depends on 70)

The method according to claim 70, wherein the infusion time is less than 3 minutes.