# US 5,700,448 A · Use of persistent free-radicals in magnetic resonance imaging

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- Number: US 5,700,448 A
- Document ID: US5700448A
- Status: Granted
- Kind: A
- Application number: 08/415,662
- Filed: 1995-04-03
- Granted: 1997-12-23
- Earliest claimed: 1991-08-09
- Assignees: Nycomed Imaging AS
- Inventors: Klaes Golman; Sven Andersson; Frode Rise; Lars-Goran Wistrand; Hakan Wikstrom
- Web page: https://patentgrep.com/patent/US5700448A

## CPC

- C07D 209/48: with oxygen atoms in positions 1 and 3, e.g. phthalimide
- A61K 49/20: containing free radicals {, e.g. trityl radical for overhauser}
- C07C 45/673: {by change of size of the carbon skeleton}
- C07C 45/70: by reaction with functional groups containing oxygen only in singly bound form
- C07C 46/00: Preparation of quinones
- C07C 49/747: containing six-membered aromatic rings
- C07C 49/753: containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups
- C07C 50/28: with monocyclic quinoid structure
- C07C 69/92: with etherified hydroxyl groups
- C07C 233/69: of an acyclic saturated carbon skeleton
- C07C 255/36: the carbon skeleton being further substituted by hydroxy groups
- C07C 255/41: the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
- C07C 309/66: Methanesulfonates
- C07C 317/22: with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C 323/20: with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07D 209/36: in position 3, e.g. adrenochrome
- C07D 215/24: attached in position 8
- C07D 311/82: Xanthenes
- C07D 339/06: having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
- C07D 471/04: Ortho-condensed systems
- C07D 493/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D 497/04: Ortho-condensed systems
- C07C 2601/16: the ring being unsaturated
- Y10T 436/24: Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

The present invention relates to the use of persistent free radicals, in particular persistent free radicals having a carbon-based .pi.-bonded electronic system available for delocalization of the unpaired electrons as image enhancing agents in magnetic resonance imaging (MRI), in particular electron spin resonance enhanced magnetic resonance imaging (ESREMRI). The invention also relates to contrast media containing such radicals and to the use of such radicals and their non-radical precursors in the manufacture of MRI and ESREMRI contrast media.

## Claims

### Claim 1

An electron spin resonance enhanced nuclear magnetic resonance imaging contrast medium comprising a physiologically tolerable, persistent, water-soluble cyclic .pi.-system free radical, said radical having an inherent linewidth in its esr spectrum of less than 500 mG, said radical having an electron delocalising .pi.-system which comprises at least one homo- or hetero- tricyclic ring, and said radical comprising at least one pair of adjacent ring carbons of a (C.dbd.C).sub.n moiety, where n is a positive integer, or an aryl substituent is substituted to form a fused ring of formula ##STR125## where X.sub.3 is oxygen, sulphur, or SO.sub.2, and Z is C(CH.sub.3).sub.2 or CR.sup.7.sub.2 wherein R.sup.7 is hydrogen or optionally hydroxylated methyl, with a center ring substituted by two oxygen atoms, together with at least one pharmacologically acceptable carrier or excipient.

### Claim 2 (depends on 1)

A contrast medium according to claim 1 wherein the radical is substituted on its skeleton by groups which are sterically hindering groups, electron donor groups, electron withdrawing groups, or solubilizing groups.

### Claim 3 (depends on 1)

A method of electron spin resonance investigation of a sample, said method comprising introducing into said sample a persistent cyclic .pi.-system radical as defined in claim 1 as a spin label.

### Claim 4 (depends on 1)

A method of magnetometric investigation of a sample, said method comprising introducing into said sample a persistent cyclic .pi.-system radical as defined in claim 1.

### Claim 5

A method of electron spin resonance enhanced nuclear magnetic resonance investigation of a sample, said method comprising introducing into said sample a persistent, water-soluble cyclic .pi.-system radical, said radical having an inherent linewidth in its esr spectrum of less than 500 mG, said radical having an electron delocalising .pi.-system which comprises at least one homo- or hetero- tricyclic ring, and said radical comprising at least one pair of adjacent ring carbons of a (C.dbd.C).sub.n moiety, where n is a positive integer, or an aryl substituent is substituted to form a fused ring of formula ##STR126## where X.sub.3 is oxygen, sulphur, or SO.sub.2, and Z is C(CH.sub.3).sup.7.sub.2 or CRT.sup.7.sub.2 wherein R.sup.7 is hydrogen or optionally hydroxylated methyl, with a center ring substituted by two oxygen atoms, together with at least one pharmacologically acceptable carrier or excipient,
exposing said sample to a first radiation of a frequency selected to excite electron spin transitions in said free radical, exposing said sample to a second radiation of a frequency selected to excite nuclear spin transitions in selected nuclei in said sample, detecting free induction decay signals from said sample, and, optionally, generating an image or dynamic flow data from said detected signals.

### Claim 6

A non-radical precursor to a physiologically tolerable, persistent, water-soluble cyclic .pi.-system free radical, said radical having an inherent linewidth in its esr spectrum of less than 500 mG, said radical having an electron delocalising .pi.-system which comprises at least one homo- or hetero- tricyclic ring, and said radical comprising at least one pair of adjacent ring carbons of a (C.dbd.C).sub.n moiety, where n is a positive integer, or an aryl substituent is substituted to form a fused ring of formula ##STR127## where X.sub.3 is oxygen sulphur, or SO.sub.2, and Z is C(CH.sub.3).sub.2 or CR.sup.7.sub.2 wherein R.sup.7 is hydrogen or optionally hydroxylated methyl, with a center ring substituted by two oxygen atoms.

### Claim 7

A process for preparing a physiologically tolerable, persistent, water-soluble cyclic .pi.-system free radical, said radical having an inherent linewidth in its esr spectrum of less than 500 mG, said radical having an electron delocalising .pi.-system which comprises at least one homo- or hetero- tricyclic ring, and said radical comprising at least one pair of adjacent ring carbons of a (C.dbd.C).sub.n moiety, where n is a positive integer, or an aryl substituent is substituted to form a fused ring of formula ##STR128## where X.sub.3 is oxygen, sulphur, or SO.sub.2, and Z is C(CH.sub.3).sub.2 or CR.sup.7.sub.2 wherein R.sup.7 is hydrogen or optionally hydroxylated methyl, with a center ring substituted by two oxygen atoms,
comprising subjecting a non-radical precursor therefor to a radical generation procedure.

### Claim 8

A persistent, water-soluble cyclic .pi.-system free radical, said radical having an inherent linewidth in its esr spectrum of less than 500 mG, said radical having an electron delocalising .pi.-system which comprises at least one homo- or hetero- tricyclic ring, and said radical comprising at least one pair of adjacent ring carbons of a (C.dbd.C).sub.n moiety, where n is a positive integer, or an aryl substituent is substituted to form a fused ring of formula ##STR129## where X.sub.3 is oxygen, sulphur, or SO.sub.2, and Z is C(CH.sub.3).sub.2 or CR.sup.7.sub.2 wherein R.sup.7 is hydrogen or optionally hydroxylated methyl, with a center ring substituted by two oxygen atoms.