# US 10,869,938 B2 · Magnetic resonance imaging

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,869,938 B2
- Document ID: US10869938B2
- Status: Granted
- Kind: B2
- Application number: 12/522,931
- Filed: 2008-01-18
- Published: 2010-07-01
- Granted: 2020-12-22
- Earliest claimed: 2007-01-18
- Assignees: 1C Targets AS
- Applicants: Per Jynge; Arne Skjold; Henrik W. Larsson
- Inventors: Per Jynge; Arne Skjold; Henrik W. Larsson
- Web page: https://patentgrep.com/patent/US10869938B2

## CPC

- A61K 49/103: {the complex-forming compound being acyclic, e.g. DTPA}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A method of determining the amount of intracellular manganese in the myocardium of an individual pre-administered with a manganese contrast agent, or a pharmaceutically acceptable salt thereof, comprising subjecting, the individual to a MRI procedure to assess the signal intensity (SI) of images, or more preferably the longitudinal relaxation rate, R1 throughout the myocardium.

## Claims

### Claim 1

A method of diagnosing cardiac remodeling and likelihood of arrhythmias and of heart failure, by a single examination in a human individual weeks to months after said individual has suffered an acute myocardial infarction, said method consisting of four consecutive steps:
(i) administering intravenously to said individual a manganese contrast agent capable of releasing manganese ions or an intact manganese contrast agent, or pharmaceutically acceptable salts thereof, for enabling uptake of manganese in cardiomyocytes of said individual;
(ii) thereafter subjecting said individual to one MRI procedure measuring a longitudinal relaxation rate, R1, or its reciprocal a longitudinal relaxation time, T1, throughout sectors and layers of the myocardium and expressing the measured R1 or T1 values in maps of said myocardium;
(iii) detecting the presence of a continuous gradient of R1 or T1 in the myocardium from a site of infarction to a region remote from said site, wherein the R1 values correlate positively and the T1 values correlate negatively to the function and viability of cardiomyocytes; and
(iv) diagnosing the individual with cardiac remodeling and likelihood of arrhythmias and heart failure when the presence of said continuous gradient in R1 or T1 is detected;
wherein the step (iii) comprises:
(a) determining whether the R1 values of the sectors or layers exhibit the continuous gradient from subnormal values at a site of infarction to supernormal values at a region remote from said site, wherein the R1 values correlate positively to the function and viability of cardiomyocytes; or
(b) determining whether the T1 values of the sectors or layers exhibit the continuous gradient from supernormal values at a site of infarction to subnormal values at a region remote from said site, wherein the T1 values correlate negatively to the function and viability of cardiomyocytes.

### Claim 2 (depends on 1)

The method as claimed in claim 1 wherein said manganese contrast agent capable of releasing manganese ions is a manganese ion releasing chelate.

### Claim 3 (depends on 2)

The method as claimed in claim 2 wherein said manganese ion releasing chelate has a Ka value in the range of 107 to 1025.

### Claim 4 (depends on 2)

The method as claimed in claim 2, wherein said manganese ion releasing chelate is a dipyridoxyl compound.

### Claim 5 (depends on 2)

The method as claimed in claim 2, wherein said manganese ion releasing chelate is a compound of formula II and salts thereof,
wherein in formula II
each R1 independently represents hydrogen or —CH2COR5;
R5 represents hydroxy, optionally hydroxylated alkoxy, amino or alkylamido;
each R2 independently represents an alkyl group substituted by one or more groups selected from hydroxyl, COOR8, CONR82, NR82, OR8, ═NR8, ═O, OP(O)(OR8)R7, OP(O)(OM)R7 and OSO3M;
R7 is OM, hydroxy, an optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group;
R8 is a hydrogen atom, or an optionally hydroxylated, optionally alkoxylated alkyl group;
M is a hydrogen atom or one equivalent of a physiologically tolerable cation;
R3 represents a C1-8 alkylene group; and
each R4 independently represents hydrogen or C1-3 alkyl.

### Claim 6 (depends on 5)

The method as claimed in claim 5, wherein each R2 independently represents a C1-6 alkyl group substituted by one or more groups selected from the group consisting of hydroxyl, COOR8, CONR82, NR82, OR8, ═NR8, ═O, OP(O)(OR8)R7, OP(O)(OM)R7 and OSO3M.

### Claim 7 (depends on 5)

The method as claimed in claim 5, wherein the physiologically tolerable cation is an alkali or alkaline earth cation, an ammonium ion or an organic amine cation.

### Claim 8 (depends on 5)

The method as claimed in claim 5, wherein R3 represents a C1-6 alkylene group.

### Claim 9 (depends on 5)

The method as claimed in claim 5, wherein R3 represents a C2-4 alkylene group.

### Claim 10 (depends on 2)

The method as claimed in claim 2, wherein said manganese ion releasing chelate has a Ka value in the range of 109 to 1024.

### Claim 11 (depends on 2)

The method as claimed in claim 2, wherein said manganese ion releasing chelate has a Ka value in the range of 1010 to 1023.

### Claim 12 (depends on 2)

The method as claimed in claim 2, wherein said manganese ion releasing chelate has a Ka value in the range of 1012 to 1022.

### Claim 13 (depends on 1)

The method as claimed in claim 1, wherein said manganese contrast agent capable of releasing manganese ions is selected from the group consisting of MnDPDP, MnDPMP and MnPLED.

### Claim 14 (depends on 1)

The method as claimed in claim 1, wherein said manganese contrast agent capable of releasing manganese ions is selected from the group consisting of MnDPMP and MnPLED.

### Claim 15 (depends on 1)

The method as claimed in claim 1, wherein said manganese contrast agent capable of releasing manganese ions is MnDPDP.

### Claim 16 (depends on 1)

The method as claimed in claim 1, wherein said manganese contrast agent capable of releasing manganese ions or an intact manganese contrast agent, or pharmaceutically acceptable salts thereof is administered in a dose of 0.5 to 40 μmol/kg bodyweight.

### Claim 17 (depends on 16)

The method as claimed in claim 16, wherein the dose is 1 to 20 μmol/kg bodyweight.

### Claim 18 (depends on 16)

The method as claimed in claim 16, wherein the dose is 2 to 10 μmol/kg bodyweight.

### Claim 19 (depends on 1)

The method as claimed in claim 1, wherein said manganese contrast agent capable of releasing manganese ions or an intact manganese contrast agent, or pharmaceutically acceptable salts thereof is administered by intravenous infusion over 1 to 30 minutes.

### Claim 20 (depends on 19)

The method as claimed in claim 19, wherein the intravenous infusion is over 2 to 20 minutes.

### Claim 21 (depends on 19)

The method as claimed in claim 19, wherein the intravenous infusion is over 5 to 10 minutes.

### Claim 22 (depends on 1)

The method as claimed in claim 1, wherein said administration of said manganese contrast agent capable of releasing manganese ions or an intact manganese contrast agent, or pharmaceutically acceptable salts thereof is conducted outside of the magnetic field used for said MRI procedure and MRI is carried out within 0.5 to 6 hours thereafter.

### Claim 23 (depends on 22)

The method as claimed in claim 22, wherein the MRI is carried out within 1 to 4 hours thereafter.

### Claim 24 (depends on 22)

The method as claimed in claim 22, wherein the MRI is carried out within 1.5 to 3 hours thereafter.

### Claim 25 (depends on 22)

The method as claimed in claim 22, wherein the MRI is carried out within 30 to 60 minutes thereafter.

### Claim 26 (depends on 1)

The method as claimed in claim 1, wherein said administration of said manganese contrast agent capable of releasing manganese ions or an intact manganese contrast agent, or pharmaceutically acceptable salts thereof is conducted inside of the magnetic field used for said MRI procedure and MRI is carried out intermittently before, during and/or thereafter.

### Claim 27 (depends on 1)

The method as claimed in claim 1 wherein said manganese contrast agent capable of releasing manganese ions is administered to said individual.

### Claim 28 (depends on 1)

The method of claim 1, wherein the number of sectors of the myocardium is 5 to 50.

### Claim 29

A method of diagnosing cardiac remodeling and likelihood of arrhythmias and of heart failure, by a single examination in a human individual weeks to months after said individual has suffered an acute myocardial infarction, said method consisting of four consecutive steps:
(i) administering intravenously to said individual a manganese contrast agent capable of releasing manganese ions or an intact manganese contrast agent, or pharmaceutically acceptable salts thereof, for enabling uptake of manganese in cardiomyocytes of said individual;
(ii) thereafter subjecting said individual to one MRI procedure measuring a signal intensity in R1 weighted images throughout sectors and layers of the myocardium and expressing the measured signal intensity in images of said myocardium;
(iii) detecting the presence of a continuous gradient of signal intensity in the myocardium from a site of infarction to a region remote from said site, wherein the signal intensity correlates positively to the function and viability of cardiomyocytes; and
(iv) diagnosing the individual with cardiac remodeling and likelihood of arrhythmias and heart failure when the presence of said continuous gradient in signal intensity is detected;
wherein the step (iii) comprises determining whether the signal intensity of the sectors or layers exhibit the continuous gradient from subnormal values at a site of infarction to supernormal values at a region remote from said site.

### Claim 30

A method of detecting a continuous gradient of a longitudinal relaxation rate or a longitudinal relaxation time in a myocardium from a site of infarction to a region remote from said site in a human individual in a single examination, said method consisting of:
(i) administering intravenously over 1 to 30 minutes a dose of 0.5 to 40 μmol/kg body weight of a chelated manganese contrast agent capable of releasing manganese ions with a Ka value in the range of 107 to 1025, or a pharmaceutically acceptable salt thereof, to said individual weeks to months after said individual has suffered an acute myocardial infarction;
(ii) subjecting said individual to one MRI procedure measuring a longitudinal relaxation rate, R1, or its reciprocal the longitudinal relaxation time, T1, throughout sectors and layers of the myocardium of said individual and expressing the measured R1 or T1 values in maps of said myocardium;
(iii) dividing the maps of R1 or T1 into transmural sectors or layers to create a composite distribution plot of R1 or T1;
(iv) detecting the presence of the continuous gradient of the R1 or T1 values of the sectors or layers in the myocardium from a site of infarction to a region remote from said site, wherein the R1 values correlate positively or the T1 values correlate negatively to the function and viability of cardiomyocytes; and
(v) diagnosing the individual with cardiac remodeling and an increased risk of arrhythmia or heart failure when the presence of said continuous gradient in R1 or T1 is detected;
wherein the step (iv) comprises:
(a) determining whether the R1 values of the sectors or layers exhibit the continuous gradient from subnormal values at a site of infarction to supernormal values at a region remote from said site, wherein the R1 values correlate positively to the function and viability of cardiomyocytes; or
(b) determining whether the T1 values of the sectors or layers exhibit the continuous gradient from supernormal values at a site of infarction to subnormal values at a region remote from said site, wherein the T1 values correlate negatively to the function and viability of cardiomyocytes.

### Claim 31

A method of assessing the risk of arrhythmias or heart failure in an individual, examined weeks to months after suffering an acute myocardial infarction, by subjecting said individual to a single diagnostic procedure to determine the presence and extent of remodeling of myocardium, said method consisting of the following four steps:
(i) administering intravenously a manganese contrast agent capable of releasing manganese ions or an intact manganese chelate contrast agent for cardiomyocyte uptake, or a pharmaceutically acceptable salt thereof, to said individual;
(ii) subjecting said individual to an MRI procedure to determine viability and function of cardiomyocytes by measuring a longitudinal relaxation rate, R1, or its reciprocal a longitudinal relaxation time, T1, throughout sectors and layers of the myocardium and mapping the measured R1 or T1 values throughout said myocardium;
(iii) detecting remodeling of myocardium by observing a continuous gradient of R1 or T1 in the myocardium from a site of infarction to a region remote from said site wherein the R1 values correlate positively and the T1 values correlate negatively to the function and viability of cardiomyocytes; and
(iv) quantifying the extent of remodeling and the risk of arrhythmias or heart failure by measuring the continuous gradient in R1 or T1;
wherein the step (iii) comprises:
(a) determining whether the R1 values of the sectors or layers exhibit the continuous gradient from subnormal values at a site of infarction to supernormal values at a region remote from said site, wherein the R1 values correlate positively to the function and viability of cardiomyocytes; or
(b) determining whether the T1 values of the sectors or layers exhibit the continuous gradient from supernormal values at a site of infarction to subnormal values at a region remote from said site, wherein the T1 values correlate negatively to the function and viability of cardiomyocytes.

### Claim 32 (depends on 31)

The method of claim 31, wherein the method assesses the risk of arrhythmias.