Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2000-01-21
2002-04-09
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009323, C424S009322, C424S009300, C424S009100
Reexamination Certificate
active
06368574
ABSTRACT:
This invention relates to magnetic resonance imaging, more particularly to use of magnetic resonance imaging in measuring tissue perfusion.
Measurements of cardiac perfusion, in particular to evaluate blood supply to the myocardium, are of importance in assessing whether patients may be at risk owing to low perfusion and whether they may benefit from preventative methods and/or treatment. Such measurements are at present typically performed using radioisotopic imaging techniques such as scintigraphy, positron emission tomography or single photon emission computed tomography; these techniques all involve injection of radioactive substances, with potential safety risks for both patients and medical staff. There is accordingly ongoing interest in the development of techniques which are less invasive and avoid radiation exposure.
Perfusion measurements in respect of other organs including, but not limited to, the kidneys and of tumour tissue are also of clinical value, e.g. for diagnostic purposes.
The use of magnetic resonance (MR) imaging in perfusion studies has received considerable attention, particularly with the development of fast and ultrafast MR imaging techniques such as fast (or turbo) spin-echo imaging, gradient-echo imaging, fast gradient recalled echo imaging, echo-planar imaging and ultrafast gradient-echo imaging, which facilitate contrast agent-enhanced dynamic imaging.
Thus, for example, Nelson et al. in
Topics in Magnetic Resonance Imaging
7(3), pp. 124-136 (1995) report use of first-pass dynamic contrast-enhanced imaging following bolus intravenous injection of MR contrast agents in assessment of cerebral perfusion. It is stated that first-pass studies rely on observation of combined T
2
and susceptibility effects (i.e. T
2
* effects), so that cerebral perfusion correlates with a decrease in signal intensity. This effect may be observed using a T
2
* susceptibility contrast agent such as a dysprosium chelate or by recording T
2
- or T
2
*-weighted scans using a predominantly positive contrast agent such as a gadolinium chelate.
Kuhl et al. in
Radiology
202(1), pp. 87-95 (1997) describe use of T
2
*-weighted dynamic first-pass perfusion imaging in differentiating benign and malignant breast tumours, with bolus injection of a gadolinium chelate. No perfusion effects were detectable in healthy breast parenchyma, and no or only minor effects were seen in fibroadenomas, whereas a strong susceptibility-mediated signal loss was observed in respect of malignant breast tumours, possibly being the result of increased flow volume and/or increased capillary flow. Conventional T
1
-weighted dynamic imaging in many instances did not distinguish between malignant tumours and fibroadenomas.
In a review entitled “Concepts of Myocardial Perfusion Imaging in Magnetic Resonance Imaging” in
Magnetic Resonance Quarterly
10 (4), pp. 249-286 (1994), Wilke et al. record that MR first-pass techniques using gadolinium chelates have been used for qualitative assessment of myocardial perfusion in patients at rest and during pharmacological stress, e.g. induced by administration of dipyridamole, and note that such techniques may be useful in obtaining quantitative information on regional myocardial blood flow and volume. First-pass imaging using gadolinium chelates and T
1
-weighted imaging sequences, e.g. an ultrafast T
1
-weighted Turbo-Flash sequence with repetition time (TR) 5.9 ms, echo time (TE) 3 ms and flip angle (&agr;) 9-15°, is described. The use of coated iron oxide particles as T
1
blood pool agents at small dosages (i.e. low concentrations) and as T
2
* susceptibility agents at higher dosages and concentrations is also discussed but there is no suggestion of first-pass applications of such contrast agents.
A disadvantage of existing first-pass MR techniques using extracellular (and preferably intravascular) gadolinium chelates and fast T
1
-weighted sequences, e.g. in cardiac perfusion imaging, is that the relatively low contrast effect of such agents may make it difficult unambiguously to identify the first pass of the contrast agent. Whilst this may to some extent be overcome by using T
2
*-weighted imaging sequences and extracellular/intravascular gadolinium- or, more preferably, dysprosium-based contrast agents, the loss in time resolution brought about by the inevitable need for longer TEs in T
2
*-weighted imaging severely limits the number of image slices which may be obtained, and may lead to significant and unacceptable motion artifacts in cardiac images.
Moreover, existing first-pass methods are not readily compatible with dual testing methods such as are needed to obtain cardiac perfusion data (i) at rest and (ii) during or after stress, since residual contrast agent from the initial bolus injection may swamp the effect of a second bolus injection intended to generate a further first-pass response.
The present invention is based on the finding that effective first pass perfusion imaging may be achieved following bolus injection of a contrast agent which exhibits simultaneous T
1
and T
2
* effects under the imaging procedure (including the contrast agent dosage and concentration) employed. Such an agent may accordingly function as both a T
1
agent and a T
2
agent under similar dosage and imaging conditions as may typically be used for conventional T
1
agents and T
1
-weighted imaging. Thus for a concentrated bolus during its first pass through vasculated tissue, a decrease in signal intensity may be observed due to the short T
2
for the concentrated bolus as well as the large additional T
2
* effect arising from confinement of the agent in the extracellular space within the vasculature. Due to the magnetic characteristics of the contrast agent, this signal decrease may be observable in a T
1
-weighted imaging sequence, giving an indication or measure of the rate of tissue/organ perfusion. Subsequent dilution of the contrast agent throughout the blood pool thereafter reduces the T
2
, and T
2
* effects, allowing the T
1
effect to dominate, thereby resulting in an increase in signal intensity, permitting an overall image of tissue/organs of interest to be obtained. Such use of a T
1
-weighted imaging sequence to visualise both T
2
* and T
1
effects is advantageous in that the short TEs characteristic of T
1
-weighted imaging ensure maximum time resolution and minimum motion artifact in the resulting images.
Thus according to one aspect of the present invention there is provided a method of contrast agent-enhanced magnetic resonance imaging of perfusion in vasculated tissue within a human or non-human animal body in which a bolus comprising a contrast-enhancing amount of a magnetic resonance imaging contrast agent is administered into the vascular system of said body, and said body is subjected to a magnetic resonance imaging procedure whereby signals or images representative of first pass of said contrast agent bolus through tissue of interest are generated, characterised in that (i) said contrast agent is capable of exhibiting simultaneous, determinable T
1
and T
2
* reducing effects under the imaging procedure employed and (ii) a T
1
-weighted imaging procedure is used (a) to visualise the first pass of said contrast agent bolus through said tissue by virtue of its signal lowering T
2
* effect and (b) to obtain a T
1
-weighted contrast agent-enhanced image of said tissue.
The method of the invention is particularly suited to cardiac imaging and measurement of myocardial perfusion, but may also be of use in, for example, measurement of renal perfusion and tumour perfusion.
In order to generate the desired balance of T
1
and T
2
* effects, the contrast agent desirably has a large magnetic moment (e.g. greater than 1000 Bohr Magnetons, preferably greater than 5000 Bohr Magnetons), and a small r
2
/r
1
ratio (where r
1
and r
2
are the T
1
and T
2
relaxivities respectively), e.g. less than 3, preferably less than 2 (as measured at 0.5 T and 40° C.). The r
2
relaxivity should also be relatively high and may advantageously be at least 10 mM
−1
Akeson Per
Johansson Lars
Amersham Health AS
Bacon & Thomas
Jones Dameron L.
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