Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2000-05-18
2003-06-03
Lateef, Marvin M. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C324S307000, C324S309000, C424S009300
Reexamination Certificate
active
06574496
ABSTRACT:
This invention relates to a method of magnetic resonance imaging (MRI), in particular to magnetic resonance imaging of deuterium and nuclei with I (nuclear spin)=½, e.g.
1
H,
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 15T 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: Bill, 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 8T, while clinical MR imaging apparatus are available with field strengths of about 0.2 to 1.5T. 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's 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 I≠O 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 ortho-deuterium enriched hydrogen (i.e.
1
H
2
or
2
H
2
gas or mixture thereof) 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 ortho-deuterium enriched hydrogen with a hydrogenatable MR imaging agent precursor, preferably a compound containing a hydrogenatable unsaturated bond and preferably a compound containing a non-zero nuclear spin nucleus, preferably a non-zero nuclear spin nucleus other than
1
H, more preferably a spin ½ (I=½) nucleus, to produce a hydrogenated (i.e. deuterated) MR imaging agent;
(ii) optionally, subjecting said hydrogenated MR imaging agent to a low magnetic field, e.g. a field of less than 50 &mgr;T, preferably less than 5 &mgr;T, more preferably less than 1 &mgr;T;
(iii) administering said hydrogenated MR imaging agent to said sample;
(iv) exposing said sample to radiation of a frequency selected to excite nuclear spin transitions of selected non-zero nuclear spin nuclei in said hydrogenated MR imaging agent;
(v) detecting magnetic resonance signals of said selected non-zero nuclear spin nuclei from said sample; and
(vi) 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.
The term “hydrogen” as used herein refers to atoms and molecules of
1
H and other hydrogen isotopes, e.g.
2
H (i.e. deuterium). “Hydrogenation” refers to reaction with a hydrogen molecule, e.g. with
1
H
2
or
2
H
2
or mixtures thereof, optionally together with other gases, generally gases not participating in the hydrogenation reaction.
1
H
2
hydrogen molecules exist in two different nuclear spin isomer forms, namely 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 deuterium molecule,
2
H
2
or D
2
, also exists, in two nuclear spin isomer forms;
ortho- and para-deuterium (herein o-D
2
and p-D
2
). However, because the deuteron is an integral spin particle (I=1) i.e. a boson, and the proton a half-integer spin particle (I=½) i.e. a fermion, the two isotopic forms possess different symmetry properties.
The total wave function of a homonuclear diatomic molecule can be written as
&psgr;
total
=&psgr;
trans
&psgr;
rot
&psgr;
vib
&psgr;
elec
&psgr;
nuc
where the indices denote contributions from translational, rotational, vibrational, electronic and nuclear wavefunctions respectively. For fermions the total wavefunction must be anti-symmetric under interchange of the two identical nuclei, but for bosons the total wavefunction must be symmetric. For both isotopic forms of hydrogen
Axelsson Oskar
Golman Klaes
Johannesson Haukur
Amersham Health AS
Lateef Marvin M.
Lin Jeoyuh
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