Paramagnetic agents for contrast-enhanced NMR imaging: a review

1209

Paramagnetic Agents for Contrast-Enhanced NMR Imaging: A Review

L

Val Jeffrey Charles C.

A.

M. Runge1 A.

Clanton1

M. Lukehart2 Leon Partain1

James,

Everette

Jr.1

The use of paramagnetic agents for contrast enhancement may extend the diagnostic potential of nuclear magnetic resonance (NMR) imaging. Proton relaxation is enhanced in targeted organ systems after either oral or intravenous administration of suitable paramagnetic agents. A decrease in TI and T2, the spin-lattice and spin-spin relaxation times, can then be observed as an increase in signal intensity on NMR imaging. Initial investigations have focused on development of agents incorporating either paramagnetic ions or stable free radicals. Principles in development and application are illustrated with examples from experiments using the Vanderbilt Technicare 0.5 1 NMR imager.

Clinical in part

evaluation of nuclear magnetic resonance (NMR) imaging has been in several centers since 1 980 [i -5]. Remarkable images, made possible by the high intrinsic contrast between tissues, have been produced of the

brain,

heart,

pursued

pelvis,

and

other

structures.

ence, several clinical investigators agents to enhance the diagnostic Unlike conventional radiography, contrast, four parameters (proton

Despite

this

impressive

initial

the

difference in intensity on NMR imaging. The pulse sequence determines the relative contribution of these factors. By imaging technique, the contrast between normal and pathologic imaging

may

be altered,

Despite

this

as is illustrated

flexibility,

certain

for

a patient

with

multiple

sclerosis

organ

systems

and

disease

states

demonstrated. For example, the gastrointestinal tract cannot sistently nor tissue vascularity and function observed directly. areas, the application of agents for contrast enhancement diagnostic potential of NMR imaging. Indeed, the differences in signal between magnetically tifying

Basic Received August 1 8, 1 983; accepted after revision September 9, 1983. 1 Department of Radiology and Radiological Sciences, Vanderbilt Nashville, TN 37232. A. E. James, Jr. 2Department

sity, Nashville,

University Address

Medical Center, reprint requests to

of Chemistry,

Vanderbilt

TN 37232.

AJR 141:1209-1215,

December

0361 -803X/83/1 416-1209 © American Roentgen Ray

Society

1983

Univer-

in figure remain

1.

poorly

be identified conIn these and other may extend the

blood-brain

barrier.

for NMR

contrast

enhancement

Principles

Pharmaceuticals

media in their basic produce a contrast not

selected for changing the tissue states

intravascular agents can enhance similar tissues, potentially iden-

of the

a breakdown

experi-

[2, 6] have commented on the use of contrast potential of the NMR technique. in which only x-ray attenuation provides density, Ti , 12, and blood flow) contribute to

significantly

and,

affect

proton

do not act as to be discussed 12, the spin-lattice

magnetic

environment.

influence

on

By definition,

neighboring

resonance

(in the

contrast media here enhance and spin-spin

thus,

materials Ti and

differ

from

iodinated

contrast

mechanism of action. In radiographic use, iodinated agents effect by absorbing x-rays. These same agents, however, do

Their

contrast

concentrations

on NMR imaging. proton relaxation relaxation times)

effect

thus

normally

used)

The paramagnetic (thereby decreasing by altering the local

is produced

indirectly

by their

nuclei.

paramagnetic

substances

possess

a permanent

magnetic

mo-

i2iO

RUNGE

Fig. 1 -Multiple sclerosis. A, GE 8800 CT scan. B and C, Technicare 0.5 T NMR transverse scans, IR 450/i 500 (B) and SE 1 20/1 000 (C) through level of atria of lateral ventricles. Lesions of multiple sclerosis are seen as

ment.

In the

magnetic externally align

absence

of an

preferentially

with

the

field.

referred

to

as

‘ ‘

AJR:141

areas of low signal intensity on IR and high signal permission from the Society of Nuclear Medicine.)

effective

magnetic

tors,

can

The

ticulate

magnetic

field,

local

produced by paramagnetic substances ation times (Ti and 12) of neighboring phenomenon

AL.

aligned. However, in an these magnetic moments

applied

moments are randomly applied magnetic field,

El

magnetic

shortens hydrogen

proton

these

field

we

parameters.

Also

oral

enhance-

the resonating

relaxation

From

terms,

are

because

neutron,

or

electrons

of the

thus, received

agents.

The

agents

that

spin

moment

than

possess

attention

The strength

mechanical

of an unpaired magnetic

greater

primary

netic centers and factors, a relation

in quantum

presence

electron).

is substantially

protons; have

paramagnetic,

unpaired

that of neutrons

unpaired

of the interaction

the hydrogen first described

(proton,

of

electron

as potential

NMR

between

nuclei by

expanded,

dL’\ \TiJ where

; is the

effective

#{128} is

spin

by:

by theory,

tion

of . This

the

is directly

paramagnetic

relation

Bboembergen fects [8, 9].

12)

is expressed

equations,

which

dependent agents

and

I (SE)

paramag-

[8]:

l(IR)

echo

the

in modifications

more

completely

of equation

describe

square 1 : the

of

their

either

the center 1 /r6. intensity

signal

the

of

on

sixth and (I) in

contrast-enhancing

in Ti

intensities

for

and 12. From spin-echo

sequences

agents. addition

ef-

(2

-

-

(SE)

are described

lR

is repetition

specific need

in Ti

on Ti

is of primary

interest.

decrease Ti will increase signal and, thus, will act as effective

intensity contrast

Thus,

the effect

and which agent,

material,

to

2

is

in Ti

minimize

of consideration,

portional

IE

a decrease

intensity.

pulse

to be chosen

and

time,

time.

sequence,

media,

intensities

The

(3)

e(TE+TI_TTl)e_nh/Tl)eTE/T2

the

will

result

in

in the development

But paramagnetic substances to Ti , a competitive effect

signal

(2)

e(TE_T’hl)eTT2

concentration,

pulse

contrast

M0(i

TI is inversion

in signal

paramagnetic

Solomon-

paramagnetic

and

Compounds that on NMR images

used

-

M0 is spin time,

For

=

= M0(i

an increase NMR

viscosity

on the concentrathe

for

12

of par-

dependence

interaction

(lR) pulse

and

development

by changes

signal

two fac-

11

contrast

of the solvent, k is Boltzman’s constant, T is the absolute temperature, ‘y is the gyromagnetic ratio (for the hydrogen nucleus), and N is the number of ions per unit volume (concentration). From equation 1 , it is apparent that a decrease in Ti (and also,

NMR

and inversion-recovery

(1 )

moment,

determine

that can be achieved

and

5kT

magnetic

may

effect

depends on several Bloembergen et al.

on by others

[9]: dipole equations

one the

the

is the inverse

of the

imaging,

Technicare,

in the

agents

nucleus

a review

on

1983

on SE. (With

of these

effect

paramagnetic interaction between the paramagnetic

NMR

where

[7]* and subsequently

contrast

the strength of the power of the distance

intensity

By selection

a greater

of importance

the relaxnuclei, a

ment.”

Substances

moment.

achieve

, December

also decrease that results in

of

12 in lower

is not desired. sequence,

carefully

decrease the effective

and

concentration

to maximize

the

in 12.

In selecting

magnetic

since the reduction in Ti Calculated Ti and 12 NMR

decrease

moment

the (.&) is

is directly proimages can be

AJR:141

, December

constructed, proposed data long,

NMR

1983

simplifying analysis of the Ti and 12 effects contrast agents. However, the time involved

acquisition precluding

and their

contrast-enhanced imaging providing

contrast

classes

those

done

that

with

that liposomes agents. Most and

affect

proton

work

has

Newhouse

loops

Brasch

NMR

blood flow only two

Little

density.

application has been

paramagnetic

intravenously

that 12.

proton

oil, and

might find work to date

12 (i.e.,

and

of bowel

mineral

for

or 12, with But practically, ,

those

Ti

to alter

depiction

oral

be produced Ti

exist, affect

with agents

al. [1 0] achieved

istered

could

density, contrast.

of compounds

and

animals

for these images is generally use in the near future in clinical

media

that affect proton its own intrinsic

density

been

analysis routine

of in

imaging.

In theory,

basic

CONTRAST

et

in experimental

[1 i ] has suggested

as vascular on materials

materials).

These

i2ii

AGENTS

TABLE

1 : Paramagnetic

Species

Metallic ions: Transition metals series: Titanium (Ti3), iron (Fe31, vanadium (V41, cobalt (Co3), chromium (Cr), nickel (Ni2), manganese (Mn21, copper (Cu25) Lanthanide series: Praseodynium (Pr3), gadolinium (Gd31, europium (Eu3), dysprosium (Dy3)

Actinide series: Protactinium (Pa45) Nitroxide stable free radicals

(NSFA):

Pyrrolidine derivatives Piperidine derivatives Molecular oxygen (02)

contrast to alter Ti

may

be admin-

or orally. EDIA decreases both the Ti magnitude of these effects being

Types of Contrast Intravascular Three

Media

Agents types

of contrast

have

been

investigated

netic

metal

ions,

and

number of these

of chemical is presented

for

nitroxide

Manganese

use

in NMR

Mn2

has

ion

with experimentally NMR imaging of

free

and

radicals

paramag-

metallic

(NSFR).

been

was

agent

injected

A large list

extensively by

several

intravenously

induced myocardial the excised hearts

corn-

a partial

investigated

contrast

as groups

in canines

infarctions. In vitro revealed a contrast

difference between infarcted and normally perfused muscle due to the lower levels of Mn25 ion in ischemic tissue. No toxicity was noted when manganese ion was injected. The use

of many

other

paramagnetic

ions

is possible,

but

the

initial interest in manganese is due to its blood kinetics and relatively high magnetic moment (table 2). This high rnagnetic moment produces a strong Ti effect with low concentrations

of manganese

clearance known

of toxicity

[1 1 ] may

ions as clinical Pararnagnetic travenous

injection

chromium-EDIA netic stability,

studies

of compounds [1 6], which

the

site free

water

is low

likely.

The

due

to their

agents

complex

can interact

and kiintact

stability with

nature

Gadolinium-DTPA

one

(fig. 2). In vitro

after

the material netic agents their [22].

West

to

toxicity. with

of

this

be

superior

Contrast Gd-DTPA

co-

vestigated potential

has

of the

intravenous

achieve

Thus, metal

gadolinium-DIPA, ion chelates/com-

to

agent

injection,

been

Cr-EDTA

in-

Because (III) ion

agent

enhancement is illustrated

the

same

because

of

in acute renal in figure 5. Con-

occurs

while

in the

obstructed

rapid

washout

of

is seen in the normal kidney. Other paramagmay prove to be superior to Gd-DTPA due to

greater relative effect on Ii The potential for development

creted

Berlin)

and other institutions [22]. moment of the gadolinium

doses

prove

tisrenal

of Cr-EDTA achieved in intensity diminishes as the

with Cr-EDTA. of paramagnetic

accumulation

kidney

The

Cr-

smaller

lesser tissue hydronephrosis

and

of EDTA)

(Schering,

vestigated at Vanderbilt of the higher magnetic

tinued

Unlike in vivo,

(and indeed

excretion of Cr-EDTA in a canine is After contrast injection, the signal is greatest initially, corresponding

to the highest level of concentration renal tissue. With time, this signal agent is cleared from the kidneys.

may

of this class of to achieve conin vivo

[20]. The renal in figure 4. of the kidneys

lexes,

is chrorniurn-EDTA. rapidly disassociates

The toxicity necessary

function illustrated intensity

after

prototype

agents

Chrornium-EDTA can be used to identify isomagnetic sue lesions, assess tissue perfusion, and quantify

as seen the class

in-

decrease in 12 tends to this interaction, a unique

need to be optimized in the use of these any paramagnetic species).

2),

in rab-

the

to concentra-

as the time to pulse repetition (IR) and the time to echo (TE), alter this relation of signal intensity to concentration (fig. 3). Thus, both the concentration and pulse technique

effects within

stable

of solutions,

concentration exists for which signal intensity (fig. 3). Variations in the pulse sequence, such

(table

use of these

seems

their

while the accompanying signal intensity. From

intermediate is maximal

12

proportional

stated previously, these two processes are A decrease in Ti results in an increase in signal

of simple

experimentally

to the pentadentate

molecules

delayed

and

usefulness

tested

is an octahedral (due

the

tissues

a high thermodynamic in vivo and being excreted

filtration [1 9]. in concentrations

Chromium-EDTA

with which

been

manifests being inert

enhancement, excretion.

ordination

have

imaging

agent of this class manganese-EDTA

trast rapid

reduce

from

[1 7, 1 8], and the future

NMR

by glomerular compounds,

However,

ions

NMR contrast agents. chelates that remain

bits and dogs in human

compounds.

paramagnetic

As

intensity, decrease

intravenously

imaging:

chelates

stable

intravenous

6].

administered

species are pararnagnetic; in table 1.

(Mn21

a potential

agents

paramagnetic

plexes,

Ii 2-i

tion [20]. competitive.

and

by the

hepatobiliary

nitroxide

stable

primarily intravascular

system free

by

radicals

Brasch NMR

as compared with of agents that are also

12 ex-

exists.

(NSFR)

and colleagues contrast agents.

have

been

in-

[1 i , 23] as Two major

subgroups of this class of compounds have been examined: the piperidine and pyrrolidine derivatives. The ring structure

i2i2

RUNGE

TABLE 2: Electronic Metal Ions Atomic No.

.

Orbital

I

and Magnetic

Electronic

Cr3 Mn2

.

t

64

Configuration

Magnetic

prigh

I arrow

.

Moment

Magnetons)

1

I

I

1VTT

I

I

I

I

s an el ectro

a spi n of + #{189}; downward

n with

(weak

field)

5.9

(weak

field)

(6.9)

I

T T

7.9

II I I I I I I denote

5,9

1.7-2.2

Dy

.

(Bohr

fl

Gd3

.

1983

Paramagnetic

I

Eu3

63

of Selected

41

I

I fl

Cu2

N ole-u

Moment

December

3.8

Fe3

66

AJR:141,

3d

25

29

AL.

on

24 26

Configuration

El

arrow

d enote

()

s an e tectron

w ith a spin

of

#{189}.

-

0

II H2

too.oooL_,

Signal

/

I

I ntensity

I

10,0001

-7/

I I ,Z_

1,000L__7i 0

CH2COO

0.1

1.0

do

0

Concentration (mmol/liter)

B

OH2 Fig.

2.-Octahedral

Fig. 3.-Interdependence sequence on signal intensity.

three-dimensional

chemical

structure

of

chromium

(Ill) ethylenediaminetetraacetate.

chromium intensity

EDTA in increasing concentration from the phantom shown in A imaged

with pulse repetition rate increases as TA decreases

of a piperidine NSFR is illustrated in figure 6. These agents have paramagnetic properties because of the presence of an unpaired

electron

that

is delocalized

between

the

nitro-

gen and oxygen atoms. This delocalization and the steric hindrance provided by adjacent bulky ligand groups stabilize the free radical in vitro. NSFR derivatives undergo in vivo

degradation

[24].

Brasch

(‘

‘TES’

major

‘)

with

by

et al. [23]

enzyme

have

a prolonged

problem

associated

systems

been

half-life with

choice of the -R group, tissue-specific the development and use of stable

and

antioxidants

imaging.

tration,

By

probes free radicals

appropriate analogous to in electronTargetpossible receptors

0.1

demonstrated

opacification but the

of iron

NSFRs.

et al. [25]

the general proposed and

spin-resonance spectroscopy may be developed. specific biomolecules also may be labeled, making contrast-enhanced study of selected tissues and by NMR

Young to provide

in vivo,

one

(TR) varied from and concentration

from left to by SE technique

to 2.5 sec. increases.

and pulse containing

right. (30

B, Signal msec TE)

Signal

intensity

Oral Agents

able to test a compound overcoming

of chromium-EDTA concentration A, SE 30/500 image of phantom

morbidity

due

use

stomach

to absorption

application of this compound. the use of ferric ammonium

still

occurs,

although

gastrointestinal

Much

the

of the

more

side promising

at a lower

effects are

of ferric after

of iron

rate,

metal

ion chelates

vive passage through the low pH ofthe stomach) particulate paramagnetic species [27]. Stable poorly

absorbed

by

t Editors note.-Ferric advertised iron supplement,

the

gastrointestinal

ammonium Geritol.

citrate

tract.

is a component

adminisprecludes

Wesbey citrate.f

correspondingly

chloride

oral

et al. [26] Absorption

with

systemic reduced.

(which

sur-

or insoluble chelates are The

portion

of the

widely

AJR:141,

December

NMR

1983

CONTRAST

AGENTS

1213

Fig. 4.-Normal canine kidneys shown by chromium EDTA. SE 30/500 at 0.5 T. Enhancement of renal tissue after intravenous injection of 0.25 mmol/kg Cr-EDTA in dog with normal renal function. Temporal

sequence:

A,

Before

injection.

C. 25 mm. D, 57 mm after injection. tions

of

adjacent

contrast

agents

to abdominal

Fig. 5.-Acute

(in

test

B, 4 mm.

Standard tubes)

solu-

are

seen

wall.

hydronephrosis

inium-DTPA. SE 30/500 mm after (B) intravenous

shown

images

before

by gadol(A)

and

21

injection of 0.25 mmol/kg Gd-DTPA in dog with surgically obstructed right ureter. Clearance of contrast by left kidney is noted with right

continued kidney.

accumulation

by

hydronephrotic

A

absorbed

is readily

to minimal toxicity. gadolinium oxalate, testinal tract intact

excreted

by glomerular

filtration,

B

leading

Insoluble metallic ion species, such as are inert and pass through the gastroinand without absorption. In this regard,

these agents resemble barium virtually no toxicity. Examples and

rectal

are

shown

administration in figures

sulfate of NMR

of paramagnetic 7 and

and should exhibit imaging after oral agents

in canines

8.

A

i214

RUNGE

El

AL.

AJR:141,

TABLE

3: NMR Contrast

Media

December

1983

Classification

Oral agents: Soluble metal ions (ferric ammonium citrate) Soluble metal ion complexes (chromium EDTA) Insoluble particulate species (gadolinium oxalate) Intravenous agents: Metal ion chelates/complexes (chromium EDTA) Nitroxide stable free radicals (‘ ‘TES”) Inhalational agents (oxygen)

OH:

OH3 I.

Note-Prototype

species

in parentheses.

0 Fig. 6.-Basic

structure

of piperidine-derivative

nitroxide

stable

free rad-

ical.

Fig. 7.-Opacification administration particulate administration.

of stomach

and colon

after

Fig. 8.-Opacification

of

chromium tris acetylacetonate, NMR contrast agent, by oral and rectal Coronal SE 30/500 image.

Inhalational Agents A brief trast

reference

agents

to the

should

two paired electrons spins do not cancel, Young et al. [25] teers and observed ventricle

(with

deoxygenated

potential

be made.

use

with parallel molecular

blood).

blood) In vitro

oxygen

con-

possesses

spin. Because these two oxygen is paramagnetic.

administered i 00% a small difference

oxygenated

of inhalational

Molecular

and

changes

oxygen to five volunin Ti between the left the right also

venticle have

(with

been

ob-

served with saline and blood substitutes due to oxygen saturation [1 7]. The implications of these findings regarding the clinical use of molecular oxygen as a contrast material in NMR

imaging

are

of small

bowel

after

oral administration

(B) SE images. Use of 0.1 sec TR of small bowel with less motion artifact

transverse resolution

cation of the

of the pancreatic duodenum, the

be determined

Intravenous

renal

from

isomagnetic can

agents

beginning

tissue

image

may

lesions

be quantified.

surrounding

make

soft tis-

could

be

the

dif-

possible

edema in the NMR imaging.

can The

finer

soft-tissue from fluid-

discrimination agents.

surrounding to confront

(A) and

allows

of the C-loop head may

tomography, to distinguish

bowel loops. This use of oral contrast contrast

Coronal

transverse

By opacification of the pancreatic

computed are difficult

of tumor from that continues

function

are only

on

and differentiated

or feces-filled made with the

dition,

unclear.

head. location

sue. In NMR, as in masses in the abdomen

ferentiation a problem

of chromium-EDTA.

(30 sec scan time) due to peristalsis.

brain, In ad-

be visualized ultimate

and

applications

to be conceived.

ACKNOWLEDGMENTS

Comment Of the several

types

the insoluble particulate metal ion chelates/complexes dia)

seem

contrast

to agents

have could

the

of paramagnetic species greatest be used

materials

(table

3),

(as oral agents) and the (as intravenous contast meimmediate in NMR

imaging

promise. for

Oral identifi-

We thank the department of Bio-Medical Physics and Bio-Engineering (Aberdeen University, Scotland), the department of Chemistry (Vanderbilt University), and the division of Radiological Sciences Technicare

(Vanderbilt (Solon,

University

Medical

School)

Ohio)

Schering

(West

and

for Berlin)

contributions; for

scientific

support; and Mary Henry for manuscript preparation and editing. Patent disclosures submitted through Vanderbilt University.

AJR:141,

December

NMR

1983

CONTRAST

observed in vivo by NMR imaging. In: Partain CL, James AE Jr, Aollo FD, Price AR, eds. Nuclear magnetic resonance (NMR) imaging. Philadelphia: Saunders, 1983:94-106.

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