Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
1999-12-13
2001-10-30
Lateef, Marvin M. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C324S307000, C324S309000
Reexamination Certificate
active
06311086
ABSTRACT:
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.
Electron spin resonance enhanced MRI, referred to herein as OMRI (Overhauser MRI) but also referred to in earlier publications as ESREMRI or PEDRI, is a method of MRI in which enhancement of the magnetic resonance signals from which images may be generated is achieved by virtue of dynamic nuclear polarization (the Overhauser effect) that occurs on VHF stimulation of an ESR transition in a magnetic (usually paramagnetic but optionally for example superparamagnetic) material (hereinafter referred to as an OMRI contrast agent) in the subject under study. Magnetic resonance signal enhancement may be by a factor of a hundred or more thus allowing OMRI images to be generated rapidly and/or with relatively low primary magnetic fields.
OMRI techniques have been described by several authors, notably Leunbach, Lurie, Ettinger, Grücker, Ehnholm and Sepponen, for example in EP-A-296833, EP-A-361551, WO-A-90/13047, J. Mag. Reson. 76:366-370(1988), EP-A-302742, SMRM 9:619(1990), SMRM 6:24(1987), SMRM 7:1094(1988), SMRM 8:329(1989), U.S. Pat. No. 4,719,425, SMRM 8:816(1989), Mag. Reson. Med. 14:140-147(1990), SMRM 9:617(1990), SMRM 9:612(1990), SMRM 9:121(1990), GB-A-2227095, DE-A-4042212 and GB-A-2220269. Res. Discl. 34833:242 (1993) (anon) discloses that contrast agents can be polarized by means of the Overhauser effect before being injected into the human body. U.S. Pat. No. 5,479,925 (Dumoulin) discloses an imaging system for obtaining vessel-selective NMR angiographic images of a subject, whilst U.S. Pat. No. 5,263,482 (Leunbach) discloses a method of and apparatus for thermographic imaging involving the use in ESREMRI of a paramagnetic contrast agent having in its esr spectrum a temperature dependent transition. One area of particular interest is the use of OMRI in determining oxygen concentrations in a sample (eg. an animate body) and this is the subject of co-pending U.S. patent application Ser. No. 08/540,146 of Leunbach.
In the basic in vivo OMRI technique, the imaging sequence involves initially irradiating a subject placed in a uniform magnetic field (the primary magnetic field, B
0
) with radiation, usually VHF radiation, of a frequency selected to excite a narrow linewidth ESR transition in an OMRI contrast agent which is in, or has been administered to, the subject. Dynamic nuclear polarization results in an increase in the population difference between the excited and ground nuclear spin states of selected nuclei, i.e. those nuclei, generally protons, which are responsible for the magnetic resonance signals (hereinafter the MR imaging nuclei). Since MR signal intensity is proportional to this population difference, the subsequent stages of each imaging sequence, performed essentially as in conventional MRI techniques, result in larger amplitude MR signals being detected. OMRI contrast agents which exhibit an ESR transition able to couple with an NMR transition of the MR imaging nuclei may be naturally present within the subject (eg. oxygen or melanin) or may be administered thereto.
Contrast agents useful in conventional methods of OMRI and suitable for in vivo administration have been reported in a number of publications. In WO-A-88/10419 (Hafslund Nycomed Innovation AB), for example, various OMRI contrast agents were proposed with particular emphasis on the use of stable nitroxide free radicals, of the chloranil semiquinone radical or of Fremy's Salt. In WO-A-90/00904 (Hafslund Nycomed Innovation AB) the use of deuterated free radicals (e.g. deuterated nitroxide free radicals) as OMRI contrast agents was proposed. WO-A-91/12024 (Nycomed Innovation AB) refers generally to the use of carbon free radicals, i.e. radicals where the unpaired electron or electrons are associated primarily with carbon atoms (for example triarylmethyl radicals where the electron charge is delocalised over a number of aromatic nuclei). More specifically, the use in OMRI of triarylmethyl radicals in which at least one aryl moiety is a sulphur-based heterocycle is the subject of WO-A-96/39367 (Nycomed Imaging AS). The use in OMRI of free radicals in which the electron charge is delocalised through a conjugated carbon-based &pgr;-system is referred to in WO-A-93/02711 (Hafslund Nycomed Innovation AB). However, OMRI contrast agents are not limited to paramagnetic organic free radicals and particulate ferromagnetic, ferrimagnetic and superparamagnetic contrast agents have been proposed in UK Patent Application No. 9605482.0, filed on Mar. 15, 1996 in the name of Nycomed Imaging AS.
To be successful as an in vivo OMRI contrast agent in conventional methods of OMRI, a chosen material must have inter alia the property of physiological tolerability. This factor alone imposes a severe limitation on the types of OMRI contrast agent which prove to be of real diagnostic utility. Organic free radicals, for example, are frequently unstable in physiological conditions or have very short half-lives leading to toxicity problems. It will often be the case that a radical found to give excellent Overhauser enhancement factors in vitro cannot be used diagnostically due to its physiological incompatibility. There is therefore a need for improved methods of OMRI which are more flexible, i.e. less constrained by physiological factors.
One particular method of OMRI of a sample is disclosed in U.K. Patent Application No. 9614139.5 filed on Jul. 5, 1996 in the name of Nycomed Imaging AS in which it is possible-to avoid administering the whole of, or substantially the whole of, an OMRI contrast agent to a sample whilst still achieving the desired Overhauser enhanced contrast effect. The method relies on ex vivo dynamic nuclear polarisation of selected nuclei of an MR imaging agent (e.g. water) by an OMRI contrast agent, the latter conveniently being disposed of prior to administration of the polarised MR imaging agent into the subject.
REFERENCES:
patent: 5263482 (1993-11-01), Leunbach
patent: 5479925 (1996-01-01), Dumoulin et al.
patent: WO 98 01766 A (1998-01-01), None
“The Use of Dynamically Polarized Contrast Agents” Research Disclosure, 348, Apr. 1993, XP002070308.
Gerfen G.J. et al., “High frequency (140 Ghz) dynamic nuclear polarization; Polarization transfer to a solute in frozen aqueous solution”, Journal of Chemical Physics, Jun. 22, 1995, XP002077806.
Ardenkjaer-Larsen Jan Henrik
Axelsson Oskar
Golman Klaes
Hansson Georg
Leunbach Ib
Bacon & Thomas
Lateef Marvin M.
Mantis Mercader Eleni
Nycomed Imaging AS
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