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WO2009022279A2 - Quinoléine en tant qu'agent de contraste dans une fluorescence induite par laser (lif) de lésions - Google Patents

Quinoléine en tant qu'agent de contraste dans une fluorescence induite par laser (lif) de lésions Download PDF

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Publication number
WO2009022279A2
WO2009022279A2 PCT/IB2008/053204 IB2008053204W WO2009022279A2 WO 2009022279 A2 WO2009022279 A2 WO 2009022279A2 IB 2008053204 W IB2008053204 W IB 2008053204W WO 2009022279 A2 WO2009022279 A2 WO 2009022279A2
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WIPO (PCT)
Prior art keywords
compound
chloroquine
quinoline
lif
lesions
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Ceased
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PCT/IB2008/053204
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English (en)
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WO2009022279A3 (fr
Inventor
Chetan Mittal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Koninklijke Philips NV
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Koninklijke Philips Electronics NV
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Publication of WO2009022279A2 publication Critical patent/WO2009022279A2/fr
Publication of WO2009022279A3 publication Critical patent/WO2009022279A3/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule

Definitions

  • the subject of this invention is to provide a compound and a contrast agent comprising a compound for a rapid, non-invasive examination process in the diagnosis of increased vascularity of lesions, especially cancerous lesions.
  • the compounds according to the present invention used for diagnosis of lesions are compounds having a quinoline ring whereas the compounds may emit fluorescence in a range from 300 to 1200 nm.
  • a method of diagnosing lesions is also subject of the present invention.
  • LIF Laser Induced Fluorescence
  • Laser induced Fluorescence is a method of diagnosis in which excitation with a specific wavelength (in the UV region) excites fluorophores in the superficial mucosal tissue and the obtained fluorescence intensity is recorded. If a known fluorescent metabolite accumulates in tumorous tissue by virtue of its increased blood supply it results in an enhanced anatomical delineation of the screening test.
  • LIF uses a point probe, which illuminates a small area (about 1 mm 2 ) for the differentiation between cancerous and normal tissue. Therefore, it becomes very time consuming to scan the whole of the mucosa (like oral mucosa or cervical mucosa). Glacial acetic acid has been used in the case of cervical mucosa [Schomacker et al, J. Biomed. Opt., 2006, 11(3), 034009)] because acetic acid turns the tumorous area white, which can be correlated with results obtained from auto- fluorescence. Unfortunately, this may not hold true for other areas.
  • diagnosis made by standard LIF does not define the cancerous areas very well.
  • the varying thickness of the keratin layer obscures diagnosis in many cases.
  • contrast agents and compounds according to the present invention circumvent problems of the prior art as they accumulate in all cancerous areas and upon UV irradiation of the mucosa, the cancerous lesions show increased fluorescence according to the present invention.
  • a contrast agent according to the present invention helps to delineate the tumour area properly and improves the results of the LIF scan.
  • quinoline derivatives as e.g. chloroquine or quinine may be used as contrast agents in LIF in order to help in a more accurate diagnosis of the areas with increased vascularity of a lesion as e.g. cancerous areas.
  • chloroquine When taken orally, chloroquine accumulates in tissue and its local concentration is higher in cancerous tissues due to the increased blood supply. Thus, cancerous tissue can be differentiated from surrounding normal tissue.
  • quinoline derivatives such as chloroquine or quinine can be used as a novel diagnostic adjunct for use together with LIF in the diagnosis of cancerous lesions.
  • Use of the inventive contrast agent aids in localising cancerous lesions and compensate for the small scanning area of the LIF probe.
  • Fig 1 Chemical structure of chloroquine with the quinoline ring
  • Fig 3 Schematic diagram showing the LIF spectra of normal mucosa
  • Fig 4 Schematic diagram showing the LIF spectra of a malignant area
  • Fig 5 Schematic diagram showing the signature of chloroquine in the LIF spectra of normal mucosa. This signature would be larger in case of malignant areas due to increased chloroquine concentration in local tissue
  • Fig 6 Structure of the quinoline ring
  • subject of the present invention is a compound having a quinoline ring whereas the compound may emit fluorescence in a range from 300 to 1200 nm, preferred from 350 to 600 nm, even more preferred around 375 nm for diagnosing an increased vascularity of a lesion.
  • a compound having a quinoline ring specifies a compound having as a core structural feature a ring system as shown in fig. 6.
  • subject of the present invention is a contrast agent for diagnosing an increased vascularity of a lesion comprising a compound having a quinoline ring whereas the compound may emit fluorescence in a range from 300 to 1200 nm, preferred from 350 to 600 nm, even more preferred around 375 nm.
  • a contrast agent according to the present invention may be one of the following: quinine, quinidine, chloroquine, amodiaquine, mefloquine, primaquine and bulaquine or derivatives thereof. Most preferred are the before-mentioned contrast agents which are clinically used as pharmaceuticals.
  • the compound is quinine or a derivative thereof.
  • the compound is chloroquine or a derivative thereof.
  • a derivative may include a compound having a quinoline ring unsubstituted or substituted by e.g. amino groups, alkyl amino groups, alkyl groups, halo groups as chloro or fluoro groups, alkoxy groups, aminoalkyl, hydroxylamino, hydroyalkyl, alkylthio, hydroxy, carboxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, non-aromatic heterocylcic ring systems, phenyl, benzyl, aromatic ring systems, heteroaromatic ring systems, arylalkyl alkylthio, aldehyde, ketone, alkylamino, imino, alkylimino, hydroxylamino, amido, imido, urethane, carbamoyl, halogen, sulfonyl, alkylsulfonyl, arylsulfon
  • all aforementioned alkyl-group-containing groups comprise an alkyl group from Ci-C ⁇ .
  • the compounds according to the present invention may be in free form or in the form of physiologically acceptable, non-toxic salts. These salts may be obtained by reacting the respective compounds with physiologically acceptable acids and bases.
  • salts include but are not limited to hydrochloride, hydrobromide, hydroiodide, hydrofluoride. nitrate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, phosphate, acid phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, isonicotinate, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, lactate, salicylate, citrate, tartrate, oxalate, malonate, suberate, sebacate, mandelate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, phenylacetate, malate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanes, glut
  • Suitable base salts include, but are not limited to, aluminium, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine salts.
  • Chloroquine derivatives may be selected from the following examples without being limited to those examples:
  • chloroquine phosphate • 7-chloro-4-(4-diethylamino-l-butylamino)quinoline (desmethylchloroquine);
  • the chloroquine derivative is selected from the group comprising: chloroquine, (-)-(7-chloro-4-(4-diethylamino-l- methylbutylamino) quinoline), chloroquine phosphate, (-)-(7-chloro-4-(4-diethylamino- 1-methylbutylamino) quinoline phosphate, hydroxychloroquine (-)-(7-chloro-4-(4- diethylamino-l-methylbutylamino)quinoline) and enantiomers thereof.
  • chloroquine enantiomers (-)- or (+)-chloroquine (7-chloro-4-(4-diethylamino-l- methylbutylamino)quinoline) may be used.
  • Compounds as quinine and chloroquine (DE 683 962) are known antimalarial drugs (for a review on chloroquine derivatives, see O'Neill PM, Pharmacol. Ther., 1998, 77(1), pp. 29-58).
  • Chloroquine ( Figure 1) has been used routinely as an antimalarial drug in high doses (10 mg base/kg body weight).
  • quinoline ring It has a quinoline ring and therefore also behaves as a fluorophore with an excitation wavelength of around 300 nm and an emission wavelength of around 375 nm.
  • a large variety of quinoline derivatives have been generated, mainly for pharmaceutical uses.
  • WO 03/093239 discloses the synthesis of quinoline analogs as antimalarial agents
  • WO 03/106424 discloses new quinoline derivatives in the context of cell-mediated immunity. When taken orally, chloroquine rapidly gets absorbed into the blood. Its bioavailability is 89% for tablets [Gustafsson et al, J. Clin. Pharmacol, 1983, 15(4), 471-479] and the half-life time of absorption is 0.56 h.
  • the peak plasma concentration is reached about 2 to 3 h after ingestion. Within the blood it is highly protein bound (46- 74%) [Adelusi et al., Gen. Pharmacol, 1982, 13(5), 433-437]. The apparent volume of distribution of chloroquine is very high (116-285 L/kg) [Gustafsson et al, J. Clin. Pharmacol, 1983, 15(4), 471-479]. This means that chloroquine rapidly distributes to the tissues. It also implies that the quenching by heme stops to occur or diminishes after a certain time when chloroquine flows out of the blood and binds to the tissues. The drug should be more concentrated in areas of increased blood supply.
  • the compound or the contrast agent according to the present invention, respectively, may be used for diagnosing cancer.
  • the compound according to the present invention may be used for diagnosing epithelial cancer.
  • epithelial cancers are oral cancer, lung cancer (through bronchoscopy), colon cancer (through colonoscopy), gastric and esophageal cancer (through endoscopy), nasopharyngeal carcinoma, cervical cancer (through colposcopy) etc.
  • the contrast agents according to the present invention may be used preferably for diagnosing lesions that can be reached through endoscopic procedures.
  • subject-matter of the present invention is the application of a compound having a quinoline ring, e.g. a chloroquine or quinine analog or derivative, and pharmaceutically acceptable salts and mixtures thereof, as contrast agent for the non-invasive monitoring of cancerous tissues.
  • a compound having a quinoline ring e.g. a chloroquine or quinine analog or derivative, and pharmaceutically acceptable salts and mixtures thereof, as contrast agent for the non-invasive monitoring of cancerous tissues.
  • the diagnosed tissue is mucosal tissue.
  • a further subject-matter of the present invention is the use of a kit comprising one or more compounds according to the present invention, having a quinoline ring, e.g. a chloroquine or quinine analog or derivative, and pharmaceutically acceptable salts and mixtures thereof in a method according to the invention.
  • Another subject-matter of the present invention is the use of a pharmaceutical composition comprising one or more compounds according to the present invention, having a quinoline ring, e.g. a chloroquine or quinine analog or derivative in a method according to the invention.
  • Subject of the present invention is a method for diagnosing an increased vascularity of a lesion comprising the steps of: • administering to a patient a compound having a quinoline ring, whereas the compound may emit fluorescence with a wavelength in a range from 300 to 1200 nm, preferred from 350 to 600 nm, even more preferred around 375 nm,
  • Another subject of the present invention is a method for obtaining an image of an area of tissue comprising the steps of: • administering to a patient a compound having a quinoline ring, whereas the compound may emit fluorescence with a wavelength in a range from 300 to 1200 nm, preferred from 350 to 600 nm, even more preferred 375 nm,
  • a patient may be a human being or an animal.
  • the compounds according to the present invention having a quinoline ring, e.g. a chloroquine or quinine analog or derivative is administered orally.
  • the method of the present invention can be used to scan a wider area of tissue, once stained with a compound according to the present invention, having a quinoline ring, e.g. a chloroquine or quinine analog or derivative, is first screened coarsely in order to quickly localise cancerous lesions. This can for instance be accomplished with the aid of a filter, which preferably only lets pass the wavelength of the emission maximum of the contrast agent according to the invention or a narrow bandwidth range around this maximum. Thereafter, identified lesions can be scanned in detail applying LIF.
  • subject of the present invention is a method according to the present invention whereas the area is visualized for fluorescence at the emission maximum of the compound according to the present invention with an appropriate filter.
  • An appropriate filter can be chosen by a person skilled in the art to ideally only let pass the desired emission maximum of the contrast agent according to the present invention or a narrow bandwidth range around this maximum.
  • monitoring can be accomplished utilizing light irradiation at a wavelength proper for the excitation of (-)- or (+)-chloroquine, which is about 275 to 325 nm.
  • the wavelength of excitation is chosen according to the excitation wavelength of the compound used.
  • the same applies for the detection wavelength which is chosen according to the emission wavelength of the compound used.
  • the method of the present invention can be used in combination with LIF (Laser Induced fluorescence).
  • LIF Laser Induced fluorescence
  • the inventive method uses the above-mentioned compounds including the preferred compounds such as e.g. quinine or chloroquine or derivatives or salts thereof as described above.
  • the inventive method is used for diagnosing cancer, especially epithelial cancer as described above.
  • monitoring of the lesion can be accomplished utilizing UV light irradiation according to a preferred embodiment of the invention.
  • a normal epithelial layer has an epithelial layer composed of cells containing NADH as fluorophore and a basement membrane (with dermis) containing collagen as fluorophore.
  • the thickness of epithelial layer increases and the basement membrane is broken due to metastasis.
  • the fluorescence signal of collagen as obtained in normal epithelium is lost in cancerous tissues due to the reasons stated above.
  • halides chloride
  • heme group in the active center of haemoglobin.
  • Haemoglobin is present only in red blood cells and therefore, once localised to tissues, heme should not quench the fluorescence emitted by chloroquine.
  • the quenching potential diminishes with decreasing size of the halide ion (I " > Br " > Cl " ).
  • F 0 is the unquenched fluorescence intensity
  • F is the fluorescence intensity at [Q]
  • [Q] is the concentration of quencher
  • K sv is the Stern- Volmer quenching constant
  • Quinine (Figure 2) is one of the chemical congeners of chloroquine. It also shows fluorescence due to the quinoline ring. Therefore, the quenching effects of chloride on the fluorescence of quinine can be very well extrapolated to the effect on chloroquine.
  • the K sv for the quenching of quinine by chlorine at 37° C is calculated to be 185 L/mol [Mayrhofer et al., http://faculty.kutztown.edu/betts/html/quench/index.htm].
  • concentration of chloride in the blood is known to be 110 mmol/L.
  • Stern- Volmer equation the fluorescence intensity of quinine would be 21 times less than the intensity without chlorine. Still, even this low intensity is sufficient for the detection with sensitive sensors. Similar results can be extrapolated for chloroquine.
  • Chloroquine itself already has an approval by the FDA, and is ubiquitously used as an antimalarial drug. It is inexpensive and easy to administer. It is, for instance, well absorbed into the body when given orally. It also is non-toxic and does not visibly colour the mucosa. That means the subject undergoing screening can very well join his/her daily activities immediately after the test as chloroquine is visible only under UV light irradiation.
  • the chloroquine derivative or analog accumulates in the tissue, the drug can act as fluorophore for LIF scans.
  • the fluorescence emitted by this contrast agent is more intense in cancerous tissue than in the surrounding normal tissue.
  • the whole mucosa, once stained with a chloroquine derivative or analog can be screened very quickly, providing for a better anatomical localisation of the cancerous lesion, which can thereafter be scanned in detail applying LIF.
  • LIF results obtained by LIF are enhanced by the use of chloroquine as contrast agent. This provides for better anatomical localization of tumour lesions.
  • the lesions can be localised by passing the fluorescence spectra through a 375 nm filter, thereby compensating for the small scanning area of LIF probes.
  • the method is independent of the localisation of the cancerous area (whether oral, cervical etc.), speeds up and facilitates diagnosis wherever LIF can be applied.
  • Chloroquine is given to the subject undergoing screening.
  • the mucosa is irradiated with light and visualised with a 375 nm filter.
  • the cancerous areas are expected to show a more intense fluorescence than the surrounding normal tissue and a threshold is selected on the basis of experiments on known carcinoma patients. The threshold would depend on the background fluorescence given by the normal mucosa.
  • Chloroquine has its emission maximum at around 375 nm which is different from the emission maxima of collagen (400 nm) and NADH (440 and 460 nm) and therefore chloroquine's signature can be very well differentiated from the spectra without chloroquine.
  • Chloroquine is administered to the subject undergoing screening according to the dosage and route of administration optimised in the research method.
  • the mucosa is irradiated with light and the fluorescence of the mucosa is visualised with a 375 nm filter.
  • the areas which show fluorescence above a standardised threshold can then be individually checked with the standard LIF procedure.
  • the contrast provided by chloroquine at 375 nm can help to better localise the cancerous area on standard LIF protocol.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'objet de la présente invention est de proposer un composé et un agent de contraste comprenant un composé permettant un rapide procédé d'examen non invasif lors du diagnostic d'une vascularité accrue de lésions, particulièrement de lésions cancéreuses. Les agents de contraste comprenant un composé et des composés utilisés à des fins de diagnostic de lésions sont des composés ayant un noyau de quinoléine tandis que les composés peuvent émettre une fluorescence dans une plage de 300 à 1200 nm. Un procédé de diagnostic de lésions fait également l'objet de la présente invention.
PCT/IB2008/053204 2007-08-15 2008-08-11 Quinoléine en tant qu'agent de contraste dans une fluorescence induite par laser (lif) de lésions Ceased WO2009022279A2 (fr)

Applications Claiming Priority (2)

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EP07114391 2007-08-15
EP07114391.1 2007-08-15

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WO2009022279A2 true WO2009022279A2 (fr) 2009-02-19
WO2009022279A3 WO2009022279A3 (fr) 2009-04-09

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Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6284223B1 (en) * 1998-10-15 2001-09-04 Fluoroprobe, Inc. Method for viewing tumor tissue located within a body cavity
US6277841B1 (en) * 2000-03-02 2001-08-21 Mallinckrodt Inc. Quinoline ligands and metal complexes for diagnosis and therapy
US20070059316A1 (en) * 2003-09-23 2007-03-15 Pallenberg Alexander J Singlet oxygen photosensitizers activated by target binding enhancing the selectivity of targeted pdt agents
US20060210479A1 (en) * 2004-08-10 2006-09-21 Dow Global Technologies Inc. Targeting chelants and chelates
WO2007067978A1 (fr) * 2005-12-09 2007-06-14 Invitrogen Corporation Agents contrastants pour imagerie optique in vivo et leurs procedes d’utilisation
AU2007244705A1 (en) * 2006-04-27 2007-11-08 Barnes-Jewish Hospital Detection and imaging of target tissue

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