Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2000-06-30
2002-10-15
Smith, Ruth S. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C600S419000, C424S009300, C324S307000, C324S309000
Reexamination Certificate
active
06466814
ABSTRACT:
This invention relates to a method of magnetic resonance imaging (MRI).
Magnetic resonance imaging (MRI) 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 the different tissue types in a subject, it has long been known to administer to the subject MR contrast agents (e.g. paramagnetic metal species) which effect relaxation times of the MR imaging nuclei in the zones in which they are administered or at which they aggregate. Contrast enhancement has also been achieved by utilising the “Overhauser effect” in which an esr transition in an administered paramagnetic species (hereinafter an OMRI contrast agent) 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 selected nuclei and thereby amplify the MR signal intensity by a factor of a hundred or more allowing OMRI images to be generated rapidly and with relatively low primary magnetic fields. Most of the OMRI contrast agents disclosed to date are radicals which are used to effect polarisation of imaging nuclei in vivo.
EP-A-0355884 (to Hafslund Nycomed Innovation AB) discloses a method of and apparatus for performing electron spin resonance enhanced magnetic resonance imaging (ESREMRI) at ultra-low fields of up to 20 Gauss. Research Disclosure No. 348, April 1993, 242 (anon) discloses that electron paramagnetic resonance can result in the enhancement of an MR signal.
Techniques are now being developed which involve ex vivo polarisation of agents containing MR imaging nuclei, prior to administration and MR signal measurement. Such techniques may involve the use of polarising agents, for example conventional OMRI contrast agents or hyperpolarised gases to achieve ex vivo polarisation of administrable MR imaging nuclei. By polarising agent is meant any agent suitable for performing ex vivo polarisation of an MR imaging agent.
The ex vivo method has inter alia the advantage that it is possible to avoid administering the whole of, or substantially the whole of, the polarising agent to the sample under investigation, whilst still achieving the desired polarisation. Thus the method is less constrained by physiological factors such as the constraints imposed by the administrability, biodegradability and toxicity of OMRI contrast agents in in vivo techniques.
It has now been found that ex vivo methods of magnetic resonance imaging may be improved by using polarised MR imaging agents comprising nuclei capable of emitting magnetic resonance signals in a uniform magnetic field (eg MR imaging nuclei such as
13
C or
15
N nuclei) and capable of exhibiting a long T
1
relaxation time, preferably additionally a long T
2
relaxation time. Such agents will be referred to hereinafter as “high T
1
agents”. Typically the molecules of a high T
1
agent will contain MR imaging nuclei in an amount greater than the natural abundance of said nuclei in said molecules (i.e. the agent will be enriched with said nuclei).
Thus viewed from one aspect the present invention provides a method of magnetic resonance investigation of a sample, preferably of a human or non-human animal body (eg. a mammalian, reptilian or avian body), said method comprising:
(i) producing a hyperpolarised solution of a high T
1
agent by dissolving in a physiologically tolerable solvent a hyperpolarised solid sample of said high T
1
agent;
(ii) where the hyperpolarisation of the solid sample of said high T
1
agent in step (i) is effected by means of a polarising agent, optionally separating the whole, substantially the whole, or a portion of said polarising agent from said high T
1
agent;
(iii) administering said hyperpolarised solution to said sample;
(iv) exposing said sample to radiation of a frequency selected to excite nuclear spin transitions in selected nuclei eg the MR imaging nuclei of the high T
1
agent;
(v) detecting magnetic resonance signals from said sample; and
(vi) optionally, generating an image, dynamic flow data, diffusion data, perfusion data, physiological data (eg. pH, PO
2
, pCO
2
, temperature or ionic concentrations) or metabolic data from said detected signals,
wherein said high T
1
agent in said hyperpolarised solution has a T
1
value (at a field strength in the range 0.01-5 T and a temperature in the range 20-40° C.) of at least 5 seconds and furthermore wherein said high T
1
agent is
13
C enriched at one or more carbonyl or quaternary carbon positions.
Thus the invention involves the sequential steps of producing a hyperpolarised solution from a hyperpolarised solid sample of a high T
1
agent comprising nuclei capable of exhibiting a long T
1
relaxation time, administration of the hyperpolarised solution of the high T
1
agent (preferably in the absence of a portion of, more preferably substantially the whole of, any polarising agent), and conventional in vivo MR signal generation and measurement. The MR signals obtained in this way may be conveniently converted by conventional manipulations into 2-, 3- or 4-dimensional data including flow, diffusion, physiological or metabolic data.
By “hyperpolarised” we mean polarised to a level over that found at room temperature and 1 T, preferably polarised to a polarisation degree in excess of 0.1%, more preferably 1%, even more preferably 10%.
Polarization is given by the equation
P
=
&LeftBracketingBar;
Nα
-
N
β
Nα
+
N
β
&RightBracketingBar;
which at equilibrium is equal to
1
-
exp
(
-
γℏ
B
o
/
kT
)
1
+
exp
(
-
γℏ
B
o
/
kT
)
where
N&agr; is the number of spins in nuclear spin state &agr; (e.g. +½);
N
&bgr;
is the number of spins in nuclear spin state &bgr; (e.g. −½);
&ggr; is the magnetogyric ratio for the isotopic nucleus in question, e.g.
13
C);
is Planck's constant divided by 2n;
B
G
is the magnetic field;
k is Boltzmann's constant; and
T is temperature in kelvin.
Thus P has a maximum value of 1 (100% polarization) and a minimum value of 0 (0% polarization).
By “physiologically tolerable solvent” we mean any solvent, solvent mixture or solution that is tolerated by the human or non-human animal body, e.g. water, aqueous solutions such as saline, perfluorocarbons, etc.
One embodiment of the invention provides a method as described above wherein the hyperpolarised solid sample of said high T
1
agent retains its polarisation when transported in a magnetic field and at low temperature; in this way the agent can be hyperpolarised at a site remote from its end use and transported to its place of use in a magnetic field and at a low temperature and there dissolved and administered.
In the embodiment referred to above, the magnetic field is preferably greater than 10 mT, more preferably greater than 0.1 T, even more preferably greater than 0.5 T, yet more preferably greater than 1 T. By “low temperature” we preferably mean lower than 80 K, more preferably lower than 4.2 K, most preferably lower than 1 K.
A further embodiment of the invention provides a method as described above wherein the hyperpolarised solution thus formed retains its polarisation when transported in a magnetic field. In this latest embodiment, the magnetic field is preferably greater than 10 mT, more preferably greater than 0.1 T, even more preferably greater than 0.5 T, yet more preferably greater than 1 T.
A yet further embodiment of the invention provides a method as described above wherein a magnetic field is present during the dissolution stage. In this latest embodiment, the magnetic field is preferably greater than 10 mT, more preferably greater than 0.1 T, even more preferably greater than 0.5 T, yet more preferably greater than 1 T.
Suitable high T
1
agents may contain nuclei
Ardenkjaer-Larsen Jan Henrik
Axelsson Oskar
Golman Klaes
Hansson Georg
Leunbach Ib
Amersham Health AS
Bacon & Thomas
Smith Ruth S.
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