Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/041—Heterocyclic compounds
  • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
  • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/04—X-ray contrast preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
  • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
  • A61K49/10—Organic compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
  • C07B59/002—Heterocyclic compounds

Definitions

• the invention relates to the use of radiolabelled glutaminyl cyclase (QC) inhibitors as imaging agents, in particular but not exclusively as medical imaging agents for the detection of neurological disorders.
• QC glutaminyl cyclase
• the invention also relates to pharmaceutical compositions comprising said radiolabelled inhibitors and to methods and kits for detecting neurological disorders. Background of the invention
• Glutaminyl cyclase catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (pGlu * ) liberating ammonia.
• pGlu * pyroglutamic acid
• Alzheimer's disease is the most common form of dementia and is an incurable, degenerative, and terminal disease. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050. Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions. Assessment of intellectual functioning including memory testing can further characterise the state of the disease.
• SPECT single photon emission computed tomography
• PET positron emission tomography
• SPECT appears to be superior in differentiating Alzheimer's disease from other possible causes, compared with the usual attempts employing mental testing and medical history analysis.
• PiB PET A new technique known as PiB PET has been developed for directly and clearly imaging ⁇ - amyloid deposits in vivo using a tracer that binds selectively to the ⁇ deposits.
• the PiB-PET compound uses 11 C PET scanning. Recent studies suggest that PiB-PET is 86% accurate in predicting which people with mild cognitive impairment will develop Alzheimer's disease within two years, and 92% accurate in ruling out the likelihood of developing Alzheimer's.
• Figure 1 shows the PET summation images (0-60 min) after administration of compound (l) d in two rats.
• Figure 2 shows the time-activity graphs in the brain of two rats (% administered dose per gram brain) after administration of compound (l) d .
• radiolabelled glutaminyl cyclase (QC) inhibitor for use as an imaging agent.
• References herein to "radiolabelled” include a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
• One non- limiting exception is 19 F, which allows detection of a molecule which contains this element without enrichment to a higher degree than what is naturally occurring.
• Compounds carrying the substituent 19 F may thus also be referred to as “labelled” or the li ke.
• the term radiolabelled may be interchangeably used with “isotopically-labelled", “labelled”, “isotopic tracer group” "isotopic marker”, “isotopic label”, “detectable isotope” or “radioligand”.
• the glutaminyl cyclase (QC) inhibitor comprises a single radiolabelled group.
• suitable, non-limiting radiolabel groups include: 2 H (D or deuterium), 3 H (T or tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 CI, 82 Br, 75 Br, 76 Br, 77 Br, 123 l, 124 l, 125 l and 131 l. It is to be understood that an isotopically labeled compound needs only to be enriched with a detectable isotope to, or above, the degree which allows detection with a technique suitable for the particular application, e.g.
• the carbon-atom of the labeled group of the labeled compound may be constituted by 12 C or other carbon-isotopes in a fraction of the molecules.
• the radionuclide that is incorporated in the radiolabelled compounds will depend on the specific application of that radiolabelled compound. For example, for in vitro plaque or receptor labelling and in competition assays, compounds that incorporate 3 H, 14 C, or 125 l will generally be most useful. For in vivo imaging applications 11 C, 13 C, 18 F, 19 F, 120 l, 123 l, 131 l, 75 Br, or 76 Br will generally be most useful.
• the radiolabel is 11 C.
• the radiolabel is 14 C.
• the radiolabel is 13 C.
• the glutaminyl cyclase (QC) inhibitor is a compound of formula (I):
• any of aforesaid heteroaryl groups may optionally be substituted by one or more groups selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 haloalkyl, -Ci_ 6thioalkyl, -SOCi -4 alkyl, -S0 2 Ci -4 alkyl, Ci -6 alkoxy-, -0-C 3-8 cycloalkyl, C 3-8 cycloalkyl, - S0 2 C 3-8 cycloalkyl, -SOC 3-6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, -C(0)Ci -6 alkyl, - C(0)OCi -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl-, nitro, halogen, cyano, hydroxyl, -C(0)OH, -NH 2 , - NHCi -4 alkyl,
• R 2 represents H , Ci -8 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, -Ci -4 alkylaryl, -Ci_ 4alkylheteroaryl, -Ci -4 alkylcarbocyclyl or -Ci -4 alkylheterocyclyl;
• any of aforesaid aryl and heteroaryl groups may optionally be substituted by one or more groups selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 haloalkyl, -Ci_ 6thioalkyl, -SOCi -4 alkyl, -S0 2 Ci -4 alkyl, Ci -6 alkoxy-, -0-C 3-8 cycloalkyl, C 3-8 cycloalkyl, - S0 2 C 3 - 8 cycloalkyl, -SOC 3-6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, -C(0)Ci -6 alkyl, - C(0)OCi -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl-, Ci- 6 alkoxy-Ci- 6 alkoxy-, nitro, halogen, haloCi.
• 6alkyl haloCi -6 alkoxy, cyano, hydroxyl, -C(0)OH, -NH 2 , -NHCi -4 alkyl, -N(Ci -4 alkyl)(Ci. 4alkyl), -N(Ci -4 alkyl)(Ci -4 alkyl)-N(Ci -4 alkyl)(Ci -4 alkyl), -Ci -4 alkyl-N(Ci -4 alkyl)(Ci -4 alkyl), - Ci -4 alkoxy-N(Ci -4 alkyl)(Ci -4 alkyl), -N(C 3-8 cycloalkyll)(C 3-8 cycloalkyl), -N(-Ci -6 alkyl-Ci.
• any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from Ci -4 alkyl, oxo, halogen, -C(0)Ci -6 alkyl and Ci -4 alkoxy;
• R 2 represents phenyl substituted by phenyl, phenyl substituted by a monocyclic heteroaryl group, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl, phenyl substituted by heterocyclyl wherein said heterocyclyl is substituted by phenyl, phenyl substituted by -0-Ci -4 alkyl-heterocyclyl, phenyl substituted by benzyloxy, phenyl substituted by carbocyclyl, phenyl substituted by carbocyclyl wherein said carbocyclyl is substituted by heterocyclyl, phenyl substituted by -O-carbocyclyl, heterocyclyl substituted by phenyl, carbocyclyl substituted by phenyl, phenyl fused to carbocyclyl, phenyl fused to heterocyclyl, -Ci -4 alkyl(phenyl substituted by phenyl), -C
• any of aforesaid phenyl, benzyloxy and heteroaryl groups may optionally be substituted by one or more groups selected from Ci -4 alkyl, halogen and Ci -4 alkoxy, and in which any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl, phenyl, oxo, halogen, hydroxyl and Ci -4 alkoxy;
• R 3 represents H, -Ci -4 alkyl or aryl;
• aryl may optionally be substituted by one or more groups selected from Ci -6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Ci -6 haloalkyl, -Ci -6 thioalkyl, -SOCi -4 alkyl, - S0 2 Ci -4 alkyl, Ci -6 alkoxy-, -0-C 3-8 cycloalkyl, C 3-8 cycloalkyl, -S0 2 C 3 - 8 cycloalkyl, -SOC 3- 6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, -C(0)Ci -6 alkyl, -C(0)OCi -6 alkyl, Ci -6 alkoxy- Ci -6 alkyl-, nitro, halogen, cyano, hydroxyl, -C(0)OH, -NH 2 , -NHCi -4 alky
• R 2 and R 3 are joined to form a carbocyclyl ring which is optionally substituted by one or more Ci -2 alkyl groups;
• R 2 and R 3 are joined to form a carbocyclyl ring which is fused to phenyl, wherein aforesaid carbocyclyl and/or phenyl may optionally be substituted by one or more groups selected from Ci -4 alkyl, halogen and Ci -4 alkoxy;
• R 2 and R 3 are joined to form a carbocyclyl ring which is fused to monocyclic heteroaryl, wherein aforesaid carbocyclyl and/or heteroaryl may optionally be substituted by one or more groups selected from Ci -4 alkyl, halogen and Ci -4 alkoxy;
• Z represents -N-R 4 , O or CHR 10 , such that when X represents O or S, Z must represent CHR 10 ;
• X and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position and which is optionally substituted by one or more halogen or Ci -2 alkyl groups;
• R 4 represents H, -Ci -8 alkyl, -C(0)Ci -6 alkyl or -NH 2 ;
• R 7 and R 8 independently represent H, -Ci -4 alkyl or aryl
• aryl may be optionally substituted by Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, Ci -6 haloalkyl, -Ci -6 thioalkyl, -SOCi -4 alkyl, -S0 2 Ci -4 alkyl, Ci -6 alkoxy-, -0-C 3- scycloalkyl, C 3-8 cycloalkyl, -S0 2 C 3-8 cycloalkyl, -SOC 3-6 cycloalkyl, C 3-6 alkenyloxy-, C 3- 6 alkynyloxy-, -C(0)Ci -6 alkyl, -C(0)OCi -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl-, nitro, halogen, cyano, hydroxyl, -C(0)OH, -NH 2 , -NHCi -4 alkyl, -N(Ci -4
• R 9 and R 10 independently represent H or methyl
• the compound of formula (I) is 1 -(1 H-benzo[d]imidazol-5-yl)-5-(4- propoxyphenyl)imidazolidin-2-one:
• the compound of formu la (l ) a is described as Example 12 in WO 2010/026212A1 (Probiodrug AG).
• the compound of formula (I) is (S)-1 -(1 H-benzo[d]imidazol-5-yl)- -(4-propoxyphenyl)imidazolidin-2-one:
• the radiolabeled compound is a compound of formula (l) c :
• the radiolabelled compound is a compound of formula (l) d :
• the radiolabelled compound is a compound of formula (l) e :
• the radiolabelled compound is a compound of formula (l) :
• the glutaminyl cyclase (QC) inhibitor is a compound of formula (II):
• R 1 represents -Ci -6 alkyl, -aryl, -Ci -6 alkylaryl, -cycloalkyl, -Ci -6 alkylcycloalkyl, -heteroaryl, -Ci_ 6 alkylheteroaryl, -heterocyclyl, -Ci -6 alkylheterocyclyl, -cycloalkyl substituted by phenyl, - cycloalkyl substituted by phenoxy, -phenyl substituted by cycloalkyl, -phenyl substituted by phenoxy, -phenyl substituted by phenyl, heterocyclyl substituted by phenyl, heteroaryl substituted by phenyl, phenyl substituted by heterocyclyl, phenyl substituted by heteroaryl, phenyl substituted by -O-cycloalkyl or phenyl substituted by -cycloalkyl-heterocyclyl
• any of aforesaid aryl, cycloalkyl, heterocyclyl, heteroaryl, phenyl or phenoxy groups may optionally be substituted by one or more groups selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 haloalkyl, -Ci -6 thioalkyl, -SOCi -4 alkyl, -S0 2 Ci.
• any of aforesaid aryl, heteroaryl or heterocyclyl groups may optionally be substituted by one or more groups selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci_ 6haloalkyl, -Ci -6 thioalkyl, -SOCi -4 alkyl, -S0 2 Ci -4 alkyl, Ci -6 alkoxy-, -0-C 3-8 cycloalkyl, C 3- scycloalkyl, -S0 2 C 3 - 8 cycloalkyl, -SOC 3-6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, - C(0)Ci -6 alkyl, -C(0)OCi -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl-, nitro, halogen, cyano, hydroxyl, - C(0)OH, -NH 2 ,
• R 3 represents Ci -6 alkyl or Ci -6 haloalkyl
• n an integer selected from 0 to 3;
• R a represents Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 haloalkyl, -Ci -6 thioalkyl, -SOCi -4 alkyl, - S0 2 Ci -4 a l kyl , Ci -6 alkoxy-, -0-C 3-8 cycloalkyl, C 3-8 cycloalkyl, -S0 2 C 3-8 cycloalkyl, -SOC 3- 6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, -C(0)Ci -6 alkyl, -C(0)OCi -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl-, nitro, halogen, cyano, hydroxyl, -C(0)OH, -NH 2 , -NHCi -4 alkyl, -N(Ci -4 alkyl)(Ci -4
• the glutaminyl cyclase (QC) inhibitor is a compound of formula (I) or formula (II) as hereinbefore defined.
• the compound of formula (II) is 1 -(1 H-Benzo[d]imidazol-6-yl)-5-(2,3- difluorophenyl)-3-methoxy-4-methyl-1 H-pyrrol-2(5H)-one:
• the compound of formula (ll) a is described as Example 8 in WO 201 1/1 10613A1 (Probiodrug AG).
• the compound of formula (II) is (R)-1 -(1 H-Benzo[d]imidazol-6-yl)-5- (2,3-difluorophenyl)-3-methoxy-4-methyl-1 H-pyrrol-2(5H)-one:
• the compound of formula (ll) b is described as Example 9 in WO 201 1/1 10613A1 (Probiodrug AG).
• the radiolabelled compound is a compound of formula (ll) c
• the radiolabelled compound is a compound of formula (ll) d :
• the glutaminyl cyclase (QC) inhibitor is a compound of formula (III):
• any of aforesaid heteroaryl groups may optionally be substituted by one or more groups selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 haloalkyl, -Ci_ 6thioalkyl, -SOCi -4 alkyl, -S0 2 Ci -4 alkyl, Ci -6 alkoxy-, -0-C 3-8 cycloalkyl, C 3-8 cycloalkyl, - S0 2 C 3-8 cycloalkyl, -SOC 3-6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, -C(0)Ci -6 alkyl, - C(0)OCi -6 alkyl, Ci- 6 alkoxy-Ci- 6 alkyl-, nitro, halogen, cyano, hydroxyl, -C(0)OH, -NH 2 , - NHCi -4 alkyl,
• any of aforesaid carbocyclyl groups may optionally be substituted by one or more groups selected from Ci -4 alkyl, oxo, halogen and Ci -4 alkoxy;
• R 2 represents Ci -8 alkyl , aryl, heteroaryl, carbocyclyl, heterocyclyl, -Ci -4 alkylaryl, -Ci_
• any of aforesaid aryl and heteroaryl groups may optionally be substituted by one or more groups selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 haloalkyl, -C 1-6 thioalkyl, -SOCi -4 alkyl, -S0 2 Ci -4 alkyl, Ci -6 alkoxy-, -0-C 3-8 cycloalkyl, C 3-8 cycloalkyl, -S0 2 C 3 - 8 cycloalkyl, -SOC 3 - 6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, -C(0)Ci -6 alkyl, -C(0)OCi -6 alkyl,
• any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from Ci -4 alkyl, oxo, halogen and Ci -4 alkoxy; or R 2 represents phenyl substituted by phenyl, phenyl substituted by a monocyclic heteroaryl group, phenyl substituted by benzyloxy, phenyl fused to carbocyclyl, phenyl fused to heterocyclyl, -Ci -4 alkyl(phenyl substituted by phenyl), -Ci -4 alkyl(phenyl substituted by a monocyclic heteroaryl group), -Ci -4 alkyl(phenyl substituted by benzyloxy), -Ci_ 4alkyl(optionally substituted phenyl fused to optionally substituted carbocyclyl or -Ci_ 4alkyl(optionally substituted phenyl fused to optionally substituted hetero;
• any of aforesaid phenyl, benzyloxy and heteroaryl groups may optionally be substituted by one or more groups selected from Ci -4 alkyl, halogen and Ci -4 alkoxy, and in which any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from Ci -4 alkyl, oxo, halogen and Ci -4 alkoxy;
• R 3 represents H, -Ci -4 alkyl or aryl;
• aryl may optionally be substituted by one or more groups selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 haloalkyl, -Ci -6 thioalkyl, -SOCi -4 alkyl, - S0 2 Ci -4 alkyl, Ci -6 alkoxy-, -0-C 3-8 cycloalkyl, C 3-8 cycloalkyl, -S0 2 C 3-8 cycloalkyl, -SOC 3- 6 cycloalkyl, C 3-6 alkenyloxy-, C 3-6 alkynyloxy-, -C(0)Ci -6 alkyl, -C(0)OCi -6 alkyl, Ci -6 alkoxy- Ci -6 alkyl-, nitro, halogen, cyano, hydroxyl, -C(0)OH, -NH 2 , -NHCi -4 alkyl, -N(
• R 2 and R 3 are joined to form a carbocyclyl ring which is optionally substituted by one or more Ci -2 alkyl groups;
• R 2 and R 3 are joined to form a carbocyclyl ring which is fused to phenyl, wherein aforesaid carbocyclyl and/or phenyl may optionally be substituted by one or more groups selected from Ci -4 alkyl, halogen and Ci -4 alkoxy; or R 2 and R 3 are joined to form a carbocyclyl ring which is fused to monocyclic heteroaryl, wherein aforesaid carbocyclyl and/or heteroaryl may optionally be substituted by one or more groups selected from Ci -4 alkyl, halogen and Ci -4 alkoxy;
• R 4 represents H, -Ci -8 alkyl, -C(0)Ci -6 alkyl or -NH 2 ;
• X represents O or S
• Y represents O or S.
• the radiolabelled glutaminyl cyclase (QC) inhibitor is a compound of formula (IV):
• the radiolabelled glutaminyl cyclase (QC) inhibitor is a compound of formula (V):
• WO 2010/1 1 1303 describes the process of labelling compounds with an 18-fluorine isotope.
• the inhibitor as defined herein is used as a medical imaging agent. In a further embodiment, the inhibitor as defined herein is used as a medical imaging agent in the detection of a neurological disorder.
• a pharmaceutical composition comprising a radiolabelled compound as defined herein or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, in combination with one or more pharmaceutically acceptable excipients.
• salts and solvates of the glutaminyl cyclase (QC) inhibitors and physiologically functional derivatives thereof which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable.
• salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds and their pharmaceutically acceptable salts and solvates.
• Suitable salts according to the invention include those formed with both organic and inorganic acids or bases.
• Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic, oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic, oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (for example p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic or naphthalenedisulfonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl
• Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and /V-methyl-D-glucamine.
• crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention.
• some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
• the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
• suitable carriers and additives may advantageously include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
• suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
• Carriers which can be added to the mixture, include necessary and inert pharmaceutical excipients, including, but not limited to, suitable binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, coatings, disintegrating agents, dyes and coloring agents.
• Soluble polymers as targetable drug carriers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolyllysine substituted with palmitoyl residue.
• the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
• biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
• Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
• the pharmaceutical composition as defined herein for use as an imaging agent in the detection of a neurological disorder.
• suitable non-limiting neurological disorders include: mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome and Huntington's disease.
• the neurological disorder is Alzheimer's disease.
• the inhibitor or composition of the invention is used in the detection of amyloid peptides.
• the inhibitor or composition of the invention is used in the detection of tau proteins of neurofibrillary tangles.
• amyloid peptides has utility in the detection and quantification of amyloid deposits and/or neurofibrillary tangles in diseases including, but not limited to Mediterranean fever, MuckleWells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile myloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Down's syndrome, Scrapie, Creutzfeldt-Jacob disease, Kuru, Gerstamnn-Straussler-Scheinker syndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid, [beta]2-microglobulin amyloid in dialysis patients, inclusionbody myositis, 32-amyloiddeposits in muscle wasting disease, chronic traumatic encephalopathy (CTE), and Islets of Langerhans diabetes Type II insulinoma.
• diseases including, but not limited to Mediterranean fever, MuckleWell
• the radiolabeled compounds of the invention may be administered by any means known to the person skilled in the art.
• administration may be local or systemic and accomplished orally, parenterally, by inhalation spray, topically, rectally, inhaled, nasally, buccally, vaginally, or via an implanted reservoir.
• parenteral as used herein includes subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, and intraosseous injection and infusion techniques.
• Dose levels can range from about 0.001 ⁇ g kg day to about 10,000 mg/kg/day. In one embodiment, the dose level is about 0.001 ⁇ g kg day to about 10 g/kg/day. I n another embodiment, the dose level is about 0.01 ⁇ g/kg/day to about 1 .0 g/kg/day. In yet another embodiment, the dose level is about 0.1 mg/kg/day to about 100 mg/kg/day.
• the exact administration protocol and dose levels will vary depending upon various factors including the age, body weight, general health, sex and diet of the patient; the determination of specific administration procedures would be routine to any one of ordinary skill in the art.
• the regimen may include pre-treatment and/or co-administration with additional compounds such as for example therapeutic agent(s).
• additional compounds such as for example therapeutic agent(s).
• a method for imaging and detection of senile plaques and/or neurofibrillary tangles in a brain tissue comprising treating the tissue with an inhibitor as defined herein for detection of neurological disorders.
• the neurological disorder is detected by measuring the affinity of an inhibitor as defined herein for senile plaques.
• the neurological disorder is detected by measuring the affinity of an inhibitor as defined herein for tau aggregates.
• a method for ex vivo or in vitro detection of amyloid deposits in a brain tissue comprising treating the tissue with an inhibitor as defined herein for detection of the amyloid deposit.
• a method for in vivo detection of amyloid deposits in a patient comprising administering an effective amount of an inhibitor as defined herein to the patient, and detecting the binding level of the compound to the amyloid deposit to the patient.
• a method for ex vivo or in vitro detection of tau proteins in a brain tissue the method comprising treating the tissue with an inhibitor as defined herein for detection of the neurofibrillary tangles.
• a method for in vivo detection of neurofibrillary tangles in a patient comprising administering an effective amount of an inhibitor as defined herein to the patient, and detecting the binding level of the compound to tau proteins.
• the method relates to detecting senile plaques and neurofibrillary tangles characteristic for a neurological disorder.
• the detection is performed using gamma imaging, magnetic resonance imaging, magnetic resonance spectroscopy or fluorescence spectroscopy.
• the detection by gamma imaging is PET or SPECT.
• Positron Emission Tomography PET is a precise and sophisticated technique using isotopes produced in a cyclotron. A positron-emitting radionuclide is introduced, usually by injection, and accumulates in the target tissue. As it decays it emits a positron, which promptly combines with a nearby electron resulting in the simultaneous emission of two identifiable gamma rays in opposite directions.
• PET farnesoid X-ray elongation spectroscopy
• SPECT single photoelectron emission computed tomography
• tracers small quantities of radiolabeled compounds, called tracers. The labeled compounds are transported, accumulated and converted in vivo in exactly the same way as the corresponding non-radioactively compound.
• Tracers, or probes can be radiolabeled with a radionuclide useful for PET imaging, such as 11 C, 13 N, 15 0, 18 F, 64 Cu and 124 l, or with a radionuclide useful for SPECT imaging, such as "Tc, 77 Br, 61 Cu, 153 Gd, 123 l, 125 l, 131 l and 32 P.
• a radionuclide useful for PET imaging such as 11 C, 13 N, 15 0, 18 F, 64 Cu and 124 l
• a radionuclide useful for SPECT imaging such as "Tc, 77 Br, 61 Cu, 153 Gd, 123 l, 125 l, 131 l and 32 P.
• PET creates images based on the distribution of molecular imaging tracers carrying positron- emitting isotopes in the tissue of the patient.
• the PET method has the potential to detect malfunction on a cellular level in the investigated tissues or organs.
• PET has been used in clinical oncology, such as for the imaging of tumors and metastases, and has been used for diagnosis of certain brain diseases, as well as mapping brain and heart function.
• SPECT can be used to complement any gamma imaging study, where a true 3D representation can be helpful, for example, imaging tumor, infection (leukocyte), thyroid or bones.
• PET positron emission tomography
• SPECT single photon emission computed tomography
• the label that is introduced into the compound can depend on the detection method desired.
• PET positron emission tomography
• SPECT single photon emission computed tomography
• the label that is introduced into the compound can depend on the detection method desired.
• the person skilled in the art is familiar with PET detection of a positron-emitting atom, such as F.
• F positron-emitting atom
• the present invention is also directed to specific compounds described herein where the F atom is replaced with a non-radiolabeled fluorine atom.
• SPECT detection of a photon-emitting atom such as 123 l or 99 Tc.
• the radiolabelled glutaminyl cyclase inhibitor of the invention should typically have sufficient radioactivity and radioactivity concentration to assure reliable diagnosis.
• the imaging of amyloid deposits and neurofibrillary tangles can also be carried out quantitatively so that the amount of amyloid deposits and neurofibrillary tangles can be determined.
• the radiolabelled glutaminyl cyclase inhibitor of the invention is introduced into a tissue or a patient in a detectable quantity.
• the compound is typically part of a pharmaceutical composition and is administered to the tissue or the patient by methods well known to those skilled in the art.
• the radiolabelled glutaminyl cyclase inhibitor of the invention is introduced into a patient in a detectable quantity and after sufficient time has passed for the compound to become associated with amyloid deposits and/or tau proteins, the labeled compound is detected non-invasively.
• the radiolabelled glutaminyl cyclase inhibitor of the invention is introduced into a patient, sufficient time is allowed for the compound to become associated with amyloid deposits, and then a sample of tissue from the patient is removed and the radiolabeled compound in the tissue is detected apart from the patient.
• a tissue sample is removed from a patient and a radiolabelled glutaminyl cyclase inhibitor of the invention is introduced into the tissue sample. After a sufficient amount of time for the compound to become bound to amyloid deposits and/or tau proteins, the compound is detected.
• a detectable quantity is a quantity of labeled compound necessary to be detected by the detection method chosen.
• the amount of radiolabelled glutaminyl cyclase inhibitor of the invention to be introduced into a patient in order to provide for detection can readily be determined by those skilled in the art. For example, increasing amounts of the radiolabeled compound can be given to a patient until the compound is detected by the detection method of choice.
• a label is introd uced into the com pou nds to provide for detection of the compounds.
• the amount of time necessary can easily be determined by introducing a detectable amount of radiolabeled glutaminyl cyclase inhibitor of the invention into a patient and then detecting the radiolabeled compound at various times after administration.
• kits for diagnosing a neurological disorder which comprises a pharmaceutical composition as defined herein and instructions to use said kit in accordance with the methods described herein.
• the reaction mixture was added dropwise to ice cold 28% ammonium hydroxide solution (15ml) with stirring.
• the product was extracted into ethyl acetate (3 x 20 ml) and the extracts were combined. After drying over sodium sulphate, the slurry was filtered and the solvent was removed under reduced pressure.
• the product was purified by flash chromatography and the required fractions were combined. The solvent was removed under reduced pressure and the remaining solid was pumped under vacuum to constant weight to give the title compound (1 .67 g, 5.22 mmol, 312 mCi).
• the catalyst was removed by filtration through a pad of Celite then washed with acetic acid (10 ml). The filtrate was evaporated to dryness under reduced pressure and toluene (20 ml) was added to the residue. The solvent was removed under reduced pressure which gave the title compound (0.75 mmol, equivalent to 45 mCi).
• the product was purified by reverse phase high performance liquid chromatography. The required fractions were combined and the organic solvent was removed under reduced pressure. To the remaining aqueous phase was added saturated sodium chloride solution (15 ml) and the product was extracted into ethyl acetate (2 x 15 ml). The extracts were combined and the solvent was removed under reduced pressure. This gave the title compound (0.098 mmol, equivalent to 5.9 mCi).
• Solvent A 0.05% trifluoroacetic acid in water
• Solvent B 0.05% trifluoroacetic acid in acetonitrile
• Solvent A 0.05% trifluoroacetic acid in water
• Solvent B 0.05% trifluoroacetic acid in acetonitrile
• the product peak containing compound (l) d was collected in 1 00ml H 2 0 and for further purification loaded onto a SepPak tc18 column.
• the SepPak tc18 column was washed with 10ml H 2 0.
• Compound (l) d was then eluted with 3ml ethanol. Thereafter the product was dried at 96 'C in an argon atmosphere.
• the final tracer solution was obtained by dissolving compound (l) d in 100 ⁇ ethanol under addition of NaCI (final concentration of ethanol max. 10%).
• HPLC Agilent HP1200 DAD incl. Autosampler and Raytest RA detector (BGO cell) Column: Chromolith Performance RP-18 endcapped 100 - 4,6 mm monolithic HPLC- column (MERCK)
• HPLC Agilent HP1 100 DAD incl. Raytest RA Detector (PET)
• Phenol-[ 13 C 6 ] (1.20 g, 12.0 mmol) was dissolved in DMSO (12 ml). Finely powdered sodium hydroxide (1.9 g, 48 mmol) was added, and was allowed to stir briskly at room temperature for 15 min. lodopropane (4.08 g, 24.0 mmol) was then added dropwise over 3 min, and the reaction mixture stirred for 30 min. The reaction was sampled for a mini workup, and analysed by GC-MS. A single peak at 6.3 min (m/z 142) indicated the reaction was complete, and was worked up by addition to chilled water (100 ml).
• the quenched reaction was extracted with hexanes (4 x 25 ml), pooled and washed in succession with a dilute sodium hydroxide solution and with brine.
• the organic extract was dried with sodium sulphate, filtered, and solvent removed in vacuo to give a syrupy product (1 .4 g, 9.9 mmol, 82%).
• the reaction was repeated using 1 .6 g phenol-[ 13 C 6 ] (16 mmol) in a similar fashion to provide 1.50 g (10.6 mmol, 66%) which was combined with the above preparation.
• the pooled title compound was used in the subsequent step without additional purification.
• Example 3 To a solution of Example 3 (0.200 g, 0.58 mmol) in dry dichloromethane at -20 ° C under an inert atmosphere was added boron tribromide (0.17 ml, 0.44 g, 1 .8 mmol) dropwise. An ice water cooling bath (0 ° C) was then used and the reaction was stirred cold for 1 h. Using a room temperature water bath, the reaction was stirred for another 1 h. The reaction was quenched by slow addition of water (18 ml). An organic layer was reserved, and was re- extracted with more water. All clear, colorless water layers (pH ⁇ 3) were combined, cooled to 5 ° C, and made basic by addition of 1 N sodium hydroxide.
• racemate compound (ll) c was purified by HPLC on a Chirobiotic TAG column eluting with 40 m M ammonium acetate : methanol (4:6). The pure isomer of (l l ) c was freeze-dried overnight yielding a white solid (1 .94 mCi, 60 mCi/mmol, 0.032 mol).
• Solvent A Phosphate buffer pH 6.0
• Solvent A 40 mM ammonium acetate buffer pH 4.0
• Rat 1 109.5 MBq of compound (l) d dissolved in 500 ⁇ 0.9% NaCI/EtOH (9/1 , v/v) were injected i.v. in the tail vein.
• the specific activity of labeled compound (l) d was 23.7 GBq/ ⁇ .
• the final dose of compound (l) d administered to rat 1 was 0.009 mg/kg.
• Rat 2 29.5 MBq compound (l) d plus 0.57 mg of the unlabelled form of compound (l) d was administered i.v. in the tail vein.
• the final dose of compound (l) d administered to rat 2 was 3.8 mg/kg.
• UV Detection 225 nm
• Activity concentrations in the rat brains (total radio activity) in plasma after the PET Scan were 0.27 %ID/g for rat 1 and 0.19 %ID/g for rat 2.

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