Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
1998-10-09
2001-08-21
Smith, Ruth S. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C324S307000, C324S309000, C424S009300
Reexamination Certificate
active
06278893
ABSTRACT:
FIELD OF THE INVNENTION
This invention relates to a method of magnetic resonance imaging (MRI).
BACKGROUND OF THE INVNENTION
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.
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 administerable 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.
SUMMARY OF THE INVENTION
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
19
F 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) subjecting a high T
1
agent to ex vivo polarisation;
(ii) optionally exposing the high T
1
agent to a uniform magnetic field (e.g. the primary field B
o
of the imaging apparatus of a weaker field e.g. 1 G or more);
(iii) where step (i) is carried out by means of a polarising agent, optionally separating the whole, substantially the whole, or a porion of said polarising agent from said high T
1
agent;
(iv) administering said high T
1
agent to said sample;
(v) exposing said sample to a second radiation of a frequency selected to excite nuclear spin transitions in selected nuclei eg the MR imaging nuclei of the high T
1
agent;
(vi) detecting magnetic resonance signals from said sample; and
(vii) optionally, generating on 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.
Thus the invention involves the sequential steps of ex vivo polarisation of a high T
1
agent comprising nuclei capable of exhibiting a long T
1
relaxation time, administration of the polarised 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.
Viewed from a further aspect the present invention provides a composition comprising a polarised
13
C or
19
F enriched compound together with one or more physiologically acceptable cariiers or excipients.
Viewed from a further aspect the present invention provides a contrast medium comprising a polarised high T
1
agent being enriched with
13
C nuclei having a T
1
relaxation time of 2 s or more in solution at magnetic fields of 0.005-10 T, together with one or more physiologically acceptable carriers or excipients.
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patent: 6125654 (2000-10-01), Honig
patent: WO 9737239 (1997-10-01), None
patent: WO 9801766 (1998-01-01), None
patent: WO 9830918 (1998-07-01), None
XP-002098873, First Observation Of A Dynamic Polarization Of Monolayers of He3Adsorbed On Fluorocarbon Microspheres, Chapellier M et al. Proceedings of the 17thInternational Conference on Low Temperature Physics, Lt-17, Karlsruhe, West Germany, Aug. 15-22, 1984, pp. 747-748 vol. 2.
XP-002098874, A Proposed Method for Polarizing Liquid3He, Langer et al., Journal of Low Temperature Physics, Nov. 1984, USA, vol. 57, No. 3-4, pp. 249-263.
XP002098966, Optically Polarized129Xe in NMR Spectroscopy, Pietrass et al., Advanced Materials, Oct. 1995, VCH Verlagsgesellschaft, Germany, vol. 7, No. 10, pp. 826-838.
Ardenkjær-Larson Jan Henrik
Axelsson Oskar
Golman Klaes
Hansson Georg
Leunbach Ib
Bacon & Thomas
Nycomed Imaging AS
Smith Ruth S.
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