Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2000-05-05
2003-06-03
Lateef, Marvin M. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C600S407000, C600S410000, C324S307000, C324S309000, C424S009300
Reexamination Certificate
active
06574495
ABSTRACT:
This invention relates to a method of magnetic resonance imaging (MRI) in particular to non-proton magnetic resonance imaging, especially of nuclei with I (nuclear spin)=½, e.g.
13
C,
15
N and
29
Si.
Magnetic resonance imaging is a diagnostic technique that has become particularly attractive to physicians as it is non-invasive and does not involve exposing the patient under study to potentially harmful radiation such as X-rays.
In order to achieve effective contrast between MR images of different tissue types, it has long been known to administer to the subject MR contrast agents (e.g. paramagnetic metal species) which affect relaxation times in the zones in which they are administered or at which they congregate. By shortening the relaxation times of the imaging nuclei (the nuclei whose MR signal is used to generate the image) the strength of the MR signal is changed and image contrast is enhanced.
MR signal strength is also dependent on the population difference between the nuclear spin states of the imaging nuclei. This is governed by a Boltzmann distribution and is dependent on temperature and magnetic field strength. However, in MR imaging contrast enhancement has also been achieved by utilising the “Overhauser effect” in which an esr transition in an administered paramagnetic species is coupled to the nuclear spin system of the imaging nuclei. The Overhauser effect (also known as dynamic nuclear polarisation) can significantly increase the population difference between excited and ground nuclear spin states of the imaging nuclei and thereby amplify the MR signal intensity. Most of the Overhauser contrast agents disclosed to date are radicals which are used to effect polarisation of imaging nuclei in vivo. There is very little reported work on techniques which involve ex vivo polarisation of imaging nuclei prior to administration and MR signal measurement.
U.S. Pat. No. 5,617,859 (Souza) discloses a magnetic resonance imaging system employing a small, high-field polarizing magnet (e.g. a 15 T magnet) to polarize a frozen material which is then warmed up and administered to a subject placed within the imaging apparatus. The material used may be water, saline, a fluorocarbon or a noble gas such as He or Xe. Since the magnetic field in the polarizing magnet is greater than that inside the imaging apparatus and since polarization is effected at low temperature, an increased population difference between the nuclear spin states (i.e. polarization) should result in a stronger MR signal from the polarized material.
In U.S. Pat. No. 5,611,340 (Souza), a somewhat similar MR imaging system is disclosed. Here however liquid hydrogen is polarized by the polarizing magnet and thereafter it is heated up and reacted with oxygen to produce polarized water which is administered to the subject. The resulting enhanced MR signal will be an enhanced
1
H MR signal.
U.S. Pat. No. 5,545,396 (Albert) discloses an in vivo MR imaging method in which a noble gas (e.g.
129
Xe or
3
He) having a hyperpolarised nuclear spin is inhaled into the lungs and a representation of its spatial distribution therein is generated. MR imaging of the human oral cavity using hyperpolarised
129
Xe was also reported by Albert in J. Mag. Res., 1996: B111, 204-207.
The use of hyperpolarised MR contrast agents in MR investigations such as MR imaging has the advantage over conventional MR techniques in that the nuclear polarisation to which the MR signal strength is proportional is essentially independent of the magnetic field strength in the MR apparatus. Currently the highest obtainable field strengths in MR imaging apparatus are about 8 T, while clinical MR imaging apparatus are available with field strengths of about 0.2 to 1.5 T. Since superconducting magnets and complex magnet construction are required for large cavity high field strength magnets, these are expensive. Using a hyperpolarised contrast agent, since the field strength is less critical it is possible to make images at all field strengths from earth field (40-50 &mgr;T) up to the highest achievable fields. However there are no particular advantages to using the very high field strengths where noise from the patient begins to dominate over electronic noise (generally at field strengths where the resonance frequency of the imaging nucleus is 1 to 20 MHz) and accordingly the use of hyperpolarised contrast agents opens the possibility of high performance imaging using low cost, low field strength magnets.
The present invention is based on a method of MRI of a sample which relies on ex vivo nuclear polarisation of selected non-hydrogen, I≠0 imaging nuclei (e.g.
13
C,
15
N and
29
Si nuclei) of an MR imaging agent by reaction of a precursor to said agent with para-hydrogen enriched hydrogen gas.
Thus viewed from one aspect the present invention provides a method of magnetic resonance investigation of a sample, preferably a human or non-human animal body (e.g. a mammalian, reptilian or avian body), said method comprising:
(i) reacting para-hydrogen enriched hydrogen with a hydrogenatable MR imaging agent precursor containing a non-zero nuclear spin nucleus other than
1
H to produce a hydrogenated MR imaging agent;
(ii) administering said hydrogenated MR imaging agent to said sample;
(iii) exposing said sample to radiation of a frequency selected to excite nuclear spin transitions of said nonzero nuclear spin nucleus in said hydrogenated MR imaging agent;
(iv) detecting magnetic resonance signals of said nonzero nuclear spin nucleus from said sample; and (v) optionally, generating an image or biological functional data or dynamic flow data from said detected signals.
The MR signals obtained in the method of the invention may be conveniently converted into 2- or 3-dimensional image data or into functional, flow or perfusion data by conventional manipulations.
Hydrogen molecules exist in two different forms, hamely para-hydrogen (p-H
2
) where the nuclear spins are antiparallel and out of phase (the singlet state) and ortho hydrogen (o-H
2
) where they are parallel or antiparallel and in phase (the triplet state). At room temperature, the two forms exist in equilibrium with a 1:3 ratio of para:ortho hydrogen. At 80K the ratio is 48:52 and at 20K it approaches 100:0, i.e. 99.8:0.2. Reducing the temperature still further is not beneficial since hydrogen freezes at about 17K. The rate of equilibration is very low in pure hydrogen but in the presence of any of several known catalysts (such as Fe
3
O
4
, Fe
2
O
3
, or activated charcoal) an equilibrium mixture is rapidly obtained and remains stable at room temperature for several hours after separation from the catalyst. Thus by “enriched hydrogen” above is meant hydrogen in which there is a higher than equilibrium proportion of para-hydrogen, for example where the proportion of para- hydrogen is more than 25%, preferably more than 30%, preferably 45% or more, more preferably 60% or more, particularly preferably 90% or more, especially preferably 99% or more. Typically the preparation of enriched hydrogen, an optional initial step in the method according to the invention, will be carried out catalytically at low temperatures e.g. at 160K or less, preferably at 80K or less or more preferably at about 20K.
The parahydrogen thus formed may be stored for long periods, preferably at low temperature, e.g. 18-20° K. Alternatively it may be stored in pressurized gas form in containers with non-magnetic and non-paramagnetic inner surfaces, e.g. a gold or deuterated polymer coated container.
Generally speaking, if a p-H
2
molecule is transferred to a host molecule by means of catalytic hydrogenation (optionally at elevated pressure (e.g. 50 to 100 bar)), the proton spins remain antiparallel and begin to relax to thermal equilibrium with the normal time constant T
1
of the hydrogen in the molecule (typically about one second). However during relaxation some of the polarisation may be transferred to neighbouring nuclei by cross-relaxation or other types of coupling. The presence of, for example, a
13
C
Axelsson Oskar
Golman Klaes
Johanneson Haukur
Mansson Sven
Olofsson Charlotte
Amersham Health AS
Bacon & Thomas
Lateef Marvin M.
Lin Jeoyuh
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