NZ614825B2 - Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system - Google Patents

Abstract

Disclosed are compounds suitable for labelling by 18F and the corresponding 18F labelled compounds themselves, 18F-fluorinated analogues thereof and their use as reference standards, methods of preparing such compounds, compositions comprising such compounds, kits comprising such compounds or compositions and uses of such compounds, compositions or kits for diagnostic imaging by Positron Emission Tomography (PET). In one embodiment the compound is (1S,2S)-2-[18F]fluoro-N-[(1,1-2H2)prop-2-yn-1-yI]indan-1-amine. In another embodiment the compound is (3aS,8aR)-3-[(1,1-2H2)prop-2-yn-1-yl]-3,3a,8,8a-tetrahydroindeno[1,2d][1,2,3}oxathiazole 2,2-dioxide. In yet another embodiment the compound is potassium N-[(1 S,2S)-2-[18F]fluoroindan-1-yl]-N-[(1,1-2H2)prop-2-yn-1-yl]sulfamate. itions and uses of such compounds, compositions or kits for diagnostic imaging by Positron Emission Tomography (PET). In one embodiment the compound is (1S,2S)-2-[18F]fluoro-N-[(1,1-2H2)prop-2-yn-1-yI]indan-1-amine. In another embodiment the compound is (3aS,8aR)-3-[(1,1-2H2)prop-2-yn-1-yl]-3,3a,8,8a-tetrahydroindeno[1,2d][1,2,3}oxathiazole 2,2-dioxide. In yet another embodiment the compound is potassium N-[(1 S,2S)-2-[18F]fluoroindan-1-yl]-N-[(1,1-2H2)prop-2-yn-1-yl]sulfamate.

Description

Compounds for use in imaging, diagnosing andlortreatment of diseases of the central nervous system Field of the invention This invention relates to novel compounds suitable for labelling by 18F and the corresponding 18F labelled compounds themselves, 19F-fluorinated analogues thereof and their use as reference standards, methods of preparing such compounds, compositions comprising such compounds, kits comprising such compounds or compositions and uses of such compounds, compositions or kits for diagnostic imaging by on Emission Tomography (PET).

Background Molecular imaging has the potential to detect disease, disease progression or therapeutic effectiveness earlier than most conventional s in the fields of oncology, neurology and cardiology. Of the several promising molecular g technologies having been developed such as optical imaging, magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET), PET is also of particular interest for drug development because of its high sensitivity and ability to e quantitative and kinetic data. on (8+) emitting isotopes e for example carbon, , fluorine, nitrogen, and oxygen. These isotopes can replace their non-radioactive counterparts in target compounds to produce tracers for PET imaging that function ically and are chemically identical to the al molecules, or can be attached to said counterparts to give close analogues of the respective parent or molecules. Among these isotopes 18F is the most convenient labelling isotope due to its relatively long half life (110 min) which permits the preparation of diagnostic tracers and uent study of biochemical processes. In addition, its low [3* energy (634 keV) is also advantageous.

The nucleophilic aromatic and aliphatic [18F]-fluoro-fluorination on is of great importance for [18F]-fluoro-labelled radiopharmaceuticals which are used as in vivo g agents targeting and visualizing diseases, e.g. solid tumours or diseases of brain. A very important technical goal in using [18F]-fluoro—labelled harmaceuticals is the quick preparation and administration of the radioactive compound.

Monoamine oxidases (MAO, EC, 1.4.3.4) represent a distinct class of amine oxidases.

Monoamine oxidases are present in two ms known as MAO-A and MAO-B (Med.

Res. Rev. 1984, 4: 323-358). Crystal ures of MAO-A and MAO-B complexed by ligands have been reported (J. Med. Chem. 2004, 47: 1767-1774 and Proc. Nat. Acad.

Sci. USA 2005, 102: 12684-12689).

In the human brain the presence of MAO-B predominates over MAO-A. Cerebral MAO-B levels increase with age and are further up-regulated in the brains of Alzheimer’s disease (AD) patients mostly due to an increase of reactive astrocytes. As astrocyte activity and, consequently, the activity of the MAO-B system is ulated in neuroinflammatory processes, radiolabelled MAO-B inhibitors may serve as an imaging biomarker in neuroinflammation and neurodegeneration, including Alzheimer’s disease.

Inhibitors that are selective for either MAO-A or MAO-B have been identified and investigated (e.g. J. Med. Chem. 2004, 47: 774 and Proc. Nat. Acad. Sci. USA, 2005, 102: 12684-12689).

Deprenyl (compound A), a MAO-B inhibitor (Biochem. Phamtacol. 1972, 5: 393-408) and line (B), a MAO-A inhibitor (Acta Psychiatr. Scand. Suppl. 1995, 386: 8-13), are potent ine oxidase inhibitors inducing irreversible inhibition of the enzymes.

The (R)-isomer of deprenyl (Selegilin®, nd (R)—A) is a more potent inhibitor than the (S)-isomer (not shown).

C13/4 Cl CH | CH Another novel potent MAO-B inhibitor recently approved for use in treatment of Parkinson’s disease is rasagiline (Azilect®, compound C) (Prog. iol. 2010, 92: 330-344).

Neuroprotective and other pharmaceutical effects have also been described for inhibitors (Curr. Pharm. Des. 2010, 16: 2799-2817, Nature Reviews Neuroscience 2006, 295: 295- 309; Br. J. col. 2006, 147: 5287-5296, J. Alzheimers Dis. 2010, 21: 361-371, Prog. Neurobiol. 2010, 92: 330-344). MAO-B inhibitors are for example used to increase DOPA levels in CNS (Progr. Drug Res. 1992, 38: 171-297) and they have been used in clinical trials for the treatment of Alzheimer’s disease (AD) based on the fact that an increased level of MAO-B is involved in astrocytes associated with Alzheimer plaques (Neuroscience 1994, 62: 15-30).

Fluorinated MAO inhibitors have been synthesised and biochemically evaluated (Kirk et al., Fluorine and Health, A. Tressaud and G. Haufe (editors), Elsevier 2008, pp. 662- 699). 18F and 11C labelled MAO inhibitors have been studied in vivo (Journal of the Neurological Science 2007, 255: 17-22; : Methods 2002, 27: 7). 18F labelled yl and deprenyl analogues (D) and (E) have also been ed (Int.

J. Radiat. Appl. Instrument. Part A, Applied Radiation es, 1991, 42: 121; J. Med.

Chem. 1990 33: 2015-2019 and Nucl. Med. Biol. 1990, 26: 111-116, respectively).

Nfl| CH CH [Li/40H 18F ed rasagiline (compound F) has been reported in WO2009/052970A2.

”III-n “/4CH Amongst said 11C labelled MAO tors, [“C]—L-Deprenyl-D2 (compound G), also referred to as DED ([11C]—L-bis-deuterium-deprenyl), has been widely used by multiple groups to study CNS diseases with regard to their impact on MAO-B acitivity, such as epilepsy (Acta Neurol. Scand. 2001, 103: 360; Acta . Scand. 1998, 98: 224; Epilepsia 1995, 36: 712), amyotrophic lateral sclerosis (ALS, see J. Neurolog. Sci. 2007, 255: 17), and traumatic brain injury (Clin. Positron Imaging 1999, 2: 71).

“CH3 er, a comparative multitracer study including compound G has been med in patients suffering from Alzheimer’s disease (AD) and healthy controls (Neurolmage 2006, 33: 588). [11C]-L-bis-deuterium-deprenyl (compound G) has been furthermore used in studies on the effect of smoking and age on MAO-B acitivity (Neurobiol. Aging 1997, 18: 431; Nucl.

Med. Biol. 2005, 32: 521; Proc. Nat. Acad. Sci. USA 2003, 20: 11600; Life Sci. 1998, 63: 2, PL19; J. Addict. Disease 1998, 17: 23).

The non-deuterated analogue of compound G [“C]—L—deprenyl binds very y and irreversibly to MAO-B. As a result, the tracer may be trapped at a rate similar to or higher than its delivery by plasma, rendering PET images of regions with high MAO-B levels and/or low blood flow representing perfusion rather than MAO-B activity. The binding of compound G is slower due to a kinetic isotope effect and thus compound G allows for a more accurate assessment of MAO-B activity as its non-deuterated counterpart (see e.g.

J. Nucl. Med. 1995, 36: 1255; J. Neurochem. 1988, 51: 1524).

However, in view of the MAO inhibitors disclosed in prior art, there is still need for novel compounds and methods for g diseases which go along with increased level of MAO enzyme, ally for novel imaging agents and methods which are easy to realize and which enable imaging certain levels of astrocyte activation and which give a or signal to background level in order to increase the ability to detect also early changes, especially e.g. in cortical regions in subjects suffering from or likely to develop dementia or in AD patients.

Problem to be solved and its solution The aim of the present invention was to provide 18F labelled compounds selectively binding to MAO-B and featuring superior signal to ound ratio as compared to the compounds disclosed in prior art. Another aim of the present invention was to provide suitable precursors for the preparation of such 18F labelled compounds.

This aim was ed by the ion of the compounds of the present invention which showed excellent uptake of the inventive 18F labelled compounds in target regions.

Surprisingly it was observed that the signal intensity caused by deuterated [18F],(2H2)rasagiline (compound 1) bound to MAO-B in target regions is up to 3 times han in case of [18F]rasagiline (compound F) at steady state. The reduced trapping rate of ated [18F],(2H2)rasagiline (compound 1) compared to [18F]rasagiline (compound F) s an improved quantification of MAO-B activity and avoids blood flow limitation of delivery of the tracer, since it is known that a high trapping rate is sible for an underestimation of the MAO-B signal in regions with high MAO-B ty. The unexpected observation is that regions with high MAO-B expression had a WO 26913 more pronounced decrease in signal intensity when compared to the effect that was expected from data published for [“C],(2H2)deprenyl (compound G) and [“C]deprenyl (compound H). The effect ly exceeds effects reported for compounds from the prior art by up to two times and hence could not be expected by the person skilled in the art.

”Ill-n ES CH HIITI \/\ X Surprisingly a reduction of the number of metabolites from eight (for [18F]rasagiline F) to two (for [18F],(2l 2)rasagiline, 1) was observed. The data hint to an improved metabolism profile of [18F],(2H2)rasagiline (1) as an advantage over the uterated compound ing to lead to less background signal in brain PET images.

Summary of the Invention This invention relates to [18F],(2H2)rasagiline unds of formula la), the 19F- fluorinated analogues thereof (compound of formula lb), to precursors (compounds of formula lc) for preparing the 18F and 19F nated compounds according to the invention, to the intermediates of formulae Id and la, and to the use of fluorinated compounds according to the invention for imaging diseases associated with altered expression of MAO-B or as reference standards, methods of preparing such compounds, compositions comprising such compounds, kits sing such compounds or itions and uses of such compounds, compositions or kits for diagnostic imaging by Positron Emission Tomography (PET). 2012/054917 F CH F CH H H // N N D D D D O—S\=O /CHD X+ 7 O X+ o -0 o 18F \S/IIZO /CH F \S//_O CH Nlj/ N D I:/D D D Id le wherein X+ is selected from the group Li+, Na+, K“, 03*, and/or Rb+.

Detailed ption of the Invention he present invention covers compounds of general formula I: (R‘XQXRZ) \ ///CH wherein (R1)(Q)(R2) is selected from the group consisting of (O)(b0nd)(3(0)2), ([18F]fluoro)(blank)(S(O)2(O')(X+)), (F)(blank)(S(O)2(O')(X+)), ([18F]fluoro)(blank)(H), and (F)(blank)(H); X+ is selected from the group consisting of a metal ion equivalent of lithium (Li), sodium (Na), potassium (K), caesium (Cs) and rubidium (Rb); including all isomeric forms of said compound, including but not d to enantiomers and diastereoisomers as well as mixtures of isomers, and any pharmaceutically acceptable salt or complex thereof.

The term “bond” as employed herein by itself or as part of r group means that the atoms or atom groups adjacent to the bond share at least one pair of electrons and thus are chemically bonded to each other.

In contrast to “bond”, the term “blank” as ed herein by itself or as part of another group means that there is neither a chemical bond nor an atom or an atom group ting the atoms adjacent to the “blank”.

The terms “19F”, “F-19”, and “F" are used synonymously herein. A compound comprising 19F, F-19, or F is a compound, which exhibits a natural fluorine isotope distribution. A person skilled in the art knows that in nature ne exists as a ne-19 isotope only. In other words, a compound comprising 19F, F-19, or F is a compound, where no efforts were made in order to enrich a certain fluorine isotope (e.g. 18F). Usually, the term “F” is used herein, however, mes the term “19F” or the term “F49” is used in order to clearly minate such a ne compound from its 18F labeled analogue.

The terms “18F” and “F-18” are used synonymously herein. A compound comprising 18F, or F-18 is a compound enriched with the isotope Fluorine-18.

The terms “D” and “H” are used synonymously herein. A compound comprising D, or 2H is a compound enriched with deuterium.

In ance with a first aspect, the present invention is directed to [18F],(2H2)rasagiline (compounds of formula la): 18F CH HWX/N D la including all isomeric forms, including but not limited to enantiomers and diastereoisomers as well as mixtures of isomers, and any pharmaceutically acceptable salt or complex thereof.

As will be shown below, the nds of formula la [18F],(2H2)rasagiline) selectively bind to MAO-B, and can be used as a tracer for PET imaging, y featuring superior signal to background ratio as compared to the compounds of prior art.

In accordance with a second aspect, the present invention is directed to compounds of formula lb: F CH H // including all ic forms, including but not limited to enantiomers and diastereoisomers as well as mixtures of isomers, and any pharmaceutically able salt or complex thereof.

The 19F analogues lb of the PET tracers la can be used as a reference standard.

In accordance with a third aspect, the present invention is directed to compounds of formula lc: O—S\=O /CHD ing all isomeric forms, ing but not limited to enantiomers and diastereoisomers as well as mixtures of isomers, and any pharmaceutically acceptable salt or complex thereof.

The compounds of formula lc can be used as precursors for the preparation of the fluorinated compounds of formulae la and lb.

In accordance with a fourth , the present invention is directed to compounds of formulae Id and le: x+ , O O 18F \//_ CH r-O // wherein X+ is selected from the group Li+, Na+, K, 05*, and/or Rb+; in a preferred embodiment of the present invention X+ is W; including all isomeric forms, including but not limited to enantiomers and diastereoisomers as well as mixtures of isomers, and any pharmaceutically acceptable salt or complex f. -0 O _ CH %-° // n X+ is selected from the group Li+, Na“, K”, Cs+, and/or Rb”; in a preferred embodiment of the present invention X+ is 05*; including all isomeric forms, including but not limited to omers and diastereoisomers as well as es of isomers, and any pharmaceutically acceptable salt or complex thereof.

The compounds of formulae Id and le are intermediates arising during preparation of compounds of formulae la and lb and/or precursors of compounds of formulae la and lb.

From the purposes of the respective compounds disclosed above, it is apparent that the compounds of formulae la, lb, lc, Id, and le are linked by the technical problem to be solved in view of prior art, i.e. the provision of improved PET tracers for MAO-B imaging, as well as by the inventive solution, and therefore form a single l inventive concept lf chiral s or other forms of isomeric centres are not otherwise d in a compound according to the present invention, all forms of such stereoisomers, including enantiomers and reoisomers, are intended to be d herein. Compounds ning chiral centres may be used as racemic mixture or as an enantiomerically ed mixture or as a diastereomeric mixture or as a diastereomerically enriched mixture, or these isomeric mixtures may be separated using well-known techniques, and an individual stereoisomer maybe used alone.

Pharmaceutically acceptable salts of the compounds according to the invention include salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, nic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Pharmaceutically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium salts and potassium salts), alkaline earth metal salts (for example calcium salts and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N- morpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

As used herein, the term “carrier” refers to microcrystalline ose, lactose, mannitol.

As used herein, the term “solvents” refers to liquid hylene glycols, ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and e water for irrigation.

As used herein, the term “stabilizers” refers to antioxidants, such as, ic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite.

"MAO-B activity" refers to an enzymatic activity that catalyzes the deamination of monoamines, i.e. neurotransmitters and bioactive amines.

Preferred compounds of a I are: ? CH H 8D”5/ D (1S,28)-2—fluoro-N-[(1,1-2H2)propynyl]indanamine ”III-n CH D D (1S,28)-2—[18F]fluoro-N-[(1,1-2H2)propynyl]indanamine aR)—3-[(1,1-2H2)propyny|]-3,3a,8,8a-tetrahydroindeno[1,2— d][1,2,3]oxathiazole 2,2—dioxide F 0 /O/ T SQ: N%i O CH caesium N-[(1S,28)—2—fluoroindan—1-y|]-N-[(1,1-2H2)propyny|]su|famate potassium N-[(18,2S)[18F]fiuoroindany|]-N-[(1,1-2H2)propyny|]su|famate In a fifth aspect, the invention is directed to a composition comprising a compound of formula I (R1)(Q)(R2) CH l7{//D wherein (R1)(Q)(R2) is selected from the group ting of (O)(b0nd)(3(0)2), ([18F]fluoro)(blank)(S(O)2(O-)(X+)), (F)(blank)(8(O)2(O-)(X+)), ([18F]fluoro)(blank)(H), and (F)(blank)(H); n X+ is selected from the group Li*, Na“, K+, Cs+ and/or Rb+; or a pharmaceutically acceptable salt of an inorganic or organic acid, a hydrate, or a complex thereof.

Preferably, the composition comprises a physiologically acceptable carrier, diluent, adjuvant or excipient.

In a first ment, the invention is directed to a composition comprising a compound of formula la and one or more pharmaceutically suitable adjuvants. These adjuvants include, inter alia, rs, solvents, and/or stabilizers. 18F CH 2012/054917 The person skilled in the art is familiar with adjuvants which are le for the desired pharmaceutical formulations, preparations or compositions on account of his/her expert knowledge.

The administration of the compounds, pharmaceutical compositions or combinations according to the invention is performed in any of the generally accepted modes of administration available in the art. Intravenous deliveries are preferred. ably, the compositions according to the invention are administered such that the dose of the active nd for imaging is in the range of 37 MBq (1 mCi) to 740 MBq (20 mCi). In particular, a dose in the range from 100 MBq to 400 MBq will be used. ably, the composition comprises (1 S,28)-2—[18F]fluoro-N-[(1 ,1-2H2)propyn yl]indanamine: null-l1 In a second embodiment, the invention is directed to a composition comprising a compound of fomtula lb.

Such composition can be used for analytical purposes. Preferably, the composition comprises (1S,ZS)fluoro-N-[(1,1-2H2)propyn—1-yl]indanamine: 2012/054917 ? H CH D D In a third embodiment, the invention is directed to a composition comprising a compound of formula lc.

O—SZO \NV/CH Such ition can be used for manufacturing of compounds of formula la and/or lb and for analytical purposes.

Preferably, the composition comprises (3aS,8aR)—3-[(1,1-2H2)propynyl]—3,3a,8,8atetrahydroindeno [1,2-d][1,2,3]oxathiazole 2,2-dioxide: O—S: In a sixth aspect, the invention is directed to methods for obtaining compounds of formula I. 2012/054917 Six methods have been identified for obtaining compounds of formula I: sis of compounds of formula Ia from compounds of formula Id The method for obtaining compounds of formula la comprises the step - reacting a compound of formula ld with acid.

The preferred features and embodiments disclosed for compounds of general formula Ia are herein incorporated.

Synthesis of compounds of formula la from compounds of formula Ic The method for ing compounds of formula Ia comprises the steps - reacting a compound of formula lc with an 18F-fluorination agent, - deprotecting the obtained compound Id for obtaining compound of formula Ia, and - optionally, converting obtained compound into a suitable salt of inorganic or organic bases, hydrates, complexes, and/or es thereof.

The preferred features and embodiments disclosed for compounds of general formula la are herein incorporated.

Synthesis of compounds of formula Id from compounds of formula lc The method for obtaining compounds of formula Ia ses the step - ng a compound of formula Ic with a 18F-fluorination agent.

The preferred features and embodiments disclosed for compounds of general formula Id are herein incorporated.

Synthesis of compounds of formula lb from compounds of formula le The method for obtaining compounds of formula lb ses the step - reacting a nd of formula le with acid.

The red features and embodiments sed for compounds of general formula lb are herein incorporated. sis of compounds of formula lb from compounds of formula lc The method for ing compounds of a lb comprises the steps - ng a compound of formula lc with a 19F-fluorination agent, - deprotecting the obtained compound for obtaining compound of formula lb, and - optionally converting obtained compound into a suitable salt of inorganic or organic bases, hydrates, complexes, and/or solvates thereof.

The red features and embodiments sed for compounds of general formula lb are herein incorporated.

Synthesis of compounds of formula le from compounds of formula lc The method for obtaining compounds of formula le comprises the step - reacting a compound of formula lc with a 1g‘F-fluorination agent.

The preferred es and embodiments disclosed for compounds of general formula le are herein incorporated. he 18l--fluorination agent can be chelated complexes known to those skilled in the art, e.g. 4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K18F (crown ether salt Kryptofix K18F), 18-crown-6 ether salt K13F, K18F, H18F, KH13F2, RblaF, Cs18F, Na18F, or tetraalkylammonium salts of 18F known to those d in the art, e.g.[lsF] tetrabutylammonium fluoride, or tetraalkylphosphonium salts of 18F known to those skilled in the art, e.g.[18F] tetrabutylphosphonium fluoride. Most preferably, the 18F- fluorination agent is Cs18F, K18F, H18F, or KH18F2, The 19F-fluorination agent is a reagent suitable for substituting the -OS(=O)2NR3R4- moiety in the compound of formula lc by a 19F atom. Such reagents are exemplified by but not limited to inorganic salts and/or adducts of hydrofluoric acid, e.g. sodium fluoride, ium fluoride, ium hydrogen difluoride, or caesium fluoride as such or in combination with chelating reagents, e.g. aminopolyether 2.2.2 (K222) ; organic salts and/or adducts of hydrofluoric acid such as tetra n—butylammonium fluoride (TBAF) or triethylamine tris-hydrofluoride; hypervalent fluorosilicates, e.g. tetrabutylammonium triphenyldifluorosilicate; sulfur fluorides, e.g. (diethylamino)sulfurtrifluoride (DAST); sulfonyl fluorides, e.g. 1,1,2,2,3,3,4,4,4-nonafluorobutanesulfony| fluoride; also electrophilic fluorination reagents are suitable to introduce 19F into organic molecules, such as ropyridinium salts, e.g. N-fluoropyridinium triflate; N-fluorosulfonimides, e.g. N-fluorobenzenesulfonimide; aliphatic N—fluoroamines derivatives, e.g. 1- chloromethylfluoro-1,4—diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®). As known to the person skilled in the art, said reagents may be used alone or in combination, e.g. 1,1,2,2,3,3,4,4,4-nonafluorobutanesu|fony| de in combination with triethylamine tris-hydrofluoride. For further methods, see publications in reach of the person d in the art, e.g. Ritter T. et al. Current Opinion in Drug Discovery & Development 2008, 11(6), 9, Kirk, K.L. Organic s Research & Development 2008, 12, 305—321, and nces cited therein.

The ts, solvents and conditions which can be used for this fluorination are common and nown to the skilled person in the field. See, e.g., S. L. Pimlott, A.

Sutherland, Chem. Soc. Rev. 2011, in press, DOI:10.1039/b922628c; Z. Li, P. S. Conti, Adv. Drug Deliv. Rev. 2010, 62, 1031; P. W. Miller, N. J. Long, R. Vilar, A. D. Gee, Angew. Chem. Int. Ed. 2008, 47, 8998; L. Cal, 8. Lu, V. W. Pike, Eur. J. Org. Chem. 2008, 2853; G. Angelini, M. Speranza, A. P. Wolf, C.-Y. Shiue, J. Fluorine Chem, 1985, 27, 177-191. Preferably, the solvents used in the present method are DMF, DMSO, acetonitrile, DMA, or mixture f, preferably the solvent is DMSO.

Embodiments and red features can be combined together and are within the scope of the invention.

In a seventh aspect, the invention also provides for an 18F-labelled compound of formulae la or a composition containing such compound for use as a diagnostic agent or imaging agent.

Preferably, the compound or ition is used as an imaging tracer or radiopharmaceutical agent for imaging es associated with altered expression of MAO-B.

Preferably, altered expression of MAO-B refers to elevated expression of MAO-B.

In other words, the invention is directed to the use of a compound of formula la for the manufacture of a radiopharmaceutical imaging tracer/agent for imaging diseases associated with elevated sion of MAO-B.

The compounds of general formula la are herein defined as above and encompass all embodiments and preferred features.

The radiopharmaceutical imaging tracer/agent is a Positron Emission Tomography (PET) suitable radiopharmaceutical imaging tracer/agent.

The invention is directed to a compound of general formula la for use in the imaging of diseases associated with elevated sion of MAO-B.

The invention is also directed to a method for imaging or diagnosing of diseases associated with elevated expression of MAO-B sing the steps: - administering to a mammal an effective amount of a composition comprising a compound of formula la, - obtaining images of the mammal and - ing images.

Preferably, mammal is human.

Preferably, the compound of general a la is (1S,28)-2—[18F]fluoro-N-[(1,1-2H2)propyn—1-yl]indan—1—amine.

Preferably, said diseases relate to inflamed CNS tissue; more preferably, said es relate to AD, multiple sclerosis and stroke; more preferably, said diseases relate to AD and multiple sclerosis; even more preferably, said diseases relate to AD.

In an eighth aspect, the invention is directed to the use of a compound of a lc as a sor for the manufacture of a radiopharmaceutical imaging tracer/agent of formula la.

O—S\=O ”7/CHD The nds of general formula Ic are herein defined as above and ass all embodiments and preferred features.

In a ninth aspect, the invention is directed to the use of compounds of general formula I, la or lb for conducting biological assays and chromatographic identification. nds of general formula lb are useful as references and/or measurement agents.

The compounds of general formula I, la and lb are herein defined as above and encompass all embodiments and preferred features.

In a tenth aspect, the invention is directed to a method for inhibiting MAO-B activity by contacting inventive compounds of formula I with proteins exhibiting MAO-B activity in- In a twelfth aspect, the present invention is directed to the use of a compound of formula I, Ia, Ib, Ic, Id or Ie in the manufacture of a diagnostic composition, in particular for PET imaging, especially of CNS es, for example Alzheimer’s disease.

General sis of comgounds of the invention Compounds of formula I can be synthesized starting e.g. from cisaminoindan—2—ol (2) (compare scheme 1). o 0 II II OH o—s\=o o—s\=o / CH NH N / 3 4 K Cs+ 7 O O 18F O // 19F o; // 7&0 /CH 5 7%0 Nfi/ I “7/CH D D D 6 18F 19F é “7/CH E HN7//CH D D D D 1 7 scheme 1 WO 26913 The amino alcohol 2 is converted to the cyclic sulphamidate 3 using sulfuryl chloride.

Tricyclic sulphamidate 3 is alkylated by (1,1-2H2)propynyl 4- methylbenzenesulfonate which can be prepared from H2)propynol (Nucl.

Med. Biol. 2001, 28 (7), 779 - 785) using tosyl anhydride. It is obvious to someone skilled in the art that the resulting sulphamidate 4 could also be obtained from 3 and (1,1-2H2)propynol by obu reaction conditions. Resulting sulphamidate 4 is converted to 18F and 19F fluorinated ic compounds 5 and 6, respectively, using potassium fluoride and caesium fluoride, respectively, or other 18F and 19F fluorinating . Aqueous hydrogenchloride is added subsequently to the reaction mixture leading to des 1 and 7, respectively. It is obvious to someone skilled in the art that also other appropriate acids are possible for this reaction, e.g. organic acids and mineral acids, e.g. sulphuric acid.

Description of the drawings Fig. 1: Cynomolgus monkeys were used to monitor [18F]rasagiline (compound F) uptake and distribution in the brain in vivo using PET. Left panel: [18F]rasagiline (compound F) is taken up in the monkey brain with ca. 280 %SUV, slightly eliminated within 15 minutes to reach ca. 225 %SUV and thereafter, increases slightly over time (by about 35 %SUV until the end of the observation time). Right panel: This panel demonstrates the time activity curves (TACs) within specific s of st, i.e. Striatum, Thalamus, Cortex and Cerebellum. Note that the TACs for the striatum and thalamus, both regions with high MAO-B activity, levelled at comparable values as did the al and cerebellar TACs, both regions with low levels of MAO-B activity, but at a lower level.

Fig. 2: Cynomolgus monkeys were used to r [18F],(2H2)rasagiline (1) uptake and distribution in the brain in vivo using PET. Left panel: [18F],(2H2)rasagiline (1) is taken up in the monkey brain with an initial amount comparable to [18F]rasagiline und F).

However, after the initial uptake the radioactivity is eliminated in a manner resembling that of a reversible ligand. Right panel: This panel demonstrates the TACs within specific regions of interest, i.e. Striatum, Thalamus, Cortex and Cerebellum. Note that the TACs for the striatum and thalamus (regions with high MAO-B activity) levelled at comparable values as did the cortical and cerebellar (regions with low MAO-B activity) TACs, but at a lower level. Also for the regions of interest investigated the elimination behaviour of the ctivity was comparable to that of a ible ligand.

Fig. 3: The brain TACs for [18F],(2H2)rasagiline (1) within the striatum, thalamus, cortex and cerebellum are shown in the left panel and compared to the brain TACs for the same regions as have been measured after pre-treatment with 0.5 mg/ kg deprenyl before injection of a comparable amount of [18F],(2H2)rasagiline (1). Note the l decrease in %SUV.

Fig. 4: The radioactivity profile of the [18F]rasagiline (compound F) as well as the profile of metabolites labelled with 18F is demonstrated. Eight metabolites were detected. The data were plotted as area% for each time point investigated calculated from the radio HPLC togram. d.c.= decay corrected Fig. 5: The radioactivity profile of [18F],(2H2)rasagiline (1) as well as the profile of metabolites ed with 18F is demonstrated. singly, only two metabolites were detected. The data were plotted as area% for each time point investigated calculated from the radio HPLC chromatogram. d.c.= decay corrected Fig. 6: The blood ctivity time curves that were corrected for the respective metabolite fractions at each time point are shown for [18F]rasagiline (compound F) and [18F],(2H2)rasagiline (1), respectively. Note the slower elimination for the di-deuterated compound (1). d.c.= decay corrected Fig. 7: PET time activity curves (TAC) sed as percent SUV of [18F],(2H2)rasagiline (1) over a time of 120 min and compared to the respective TACs of non-deuterated [18F]rasagiline (compound F). Surprisingly, the decrease of the signal of [18F],(2H2)rasagiline (1), as expressed as % standard uptake value (SUV) in TACs compared to the signal of the non-deuterated [18F]rasagiline (compound F) was 2.4 to 3 times between 30 and 120 min in the igated brain regions of cynomolgus monkeys. This was not expected since the decrease in signal due to the ation effect known from [“C]deprenyl (compound H) versus [“C],(2H2)deprenyl (compound G) is only approximately 1.2 — 2.0 times ed in baboon and human brain regions comparable to those investigated by us, e.g. striatum, thalamus, cortex r et al. J.

Neurochem. 1988, 51: 1524-1534; J. Nucl. Med. 1995, 36: 1255-1262; Mol. g Biol. 2005, 7: 377-387). hus, the brain trapping also in target regions was less pronounced and leads to an advantage over [“C],(2H2)deprenyl (compound G) regarding background signal.

Fig. 8: Graphic visualization of the effect of deuteration of [13F]rasagiline for signal retention in target (thalamus and striatum) and non-target (cerebellum) areas as compared to the effect of deuteration of [“C]deprenyl reported in the literature.

Fig. 9: ical HPLC chromatogram of deuterated [13F],(2H2)rasagiline example 3 (gamma detection) Fig. 10: Analytical HPLC chromatogram of deuterated [18F],(2H2)rasagiline example 2 (UV detection) Table 1: Data which are graphically ed in Fig. 4 Table 2: Data which are graphically depicted in Fig. 5 Experimental section General: All solvents and chemicals were obtained from commercial sources and used without further purification if not stated otherwise. The following table lists the abbreviations used in this aph and in the Examples section as far as they are not explained within the text body.

Cl chemical tion d t (in NMR) dd doublet of t DMF N,N-dimethylformamide DlVlSO dimethylsulfoxide ESI electrospray ionisation EtOAc ethyl acetate h hour K2003 potassium carbonate K222 4, 7, 13, 16, 21, 24-hexaoxa-1,10- diazabicyclo[8.8.8]-hexacosane MeCN acetonitrile MS mass spectrometry m multiplet min minute NMR nuclear magnetic resonance spectroscopy : chemical shifts (6) are given in ppm. r.t. room temperature singlet sec second t triplet td triplet of doublet __J Abbreviations NMR peak forms are stated as they appear in the spectra, possible higher order s have not been considered.

The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In certain cases, the compounds may be ed by crystallization. In some cases, impurities may be removed by trituration using a le solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel dges, e.g. from is such as lsolute® Flash silica gel or lsolute® Flash NH2 silica gel in combination with e.g. a FlashMaster ll autopurifier (Argonaut/Biotage) and eluents such as gradients of hexane/EtOAc or dichloromethane/ethanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters auto purifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may n additives such as trifluoroacetic acid or aqueous ammonia. In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic functionality in the form of a salt, such as, in the case of a nd of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example. A salt of this type may be ormed into its free base form, respectively, by s methods known to the person skilled in the art. ation of Intermediates Intermediate 1A: (1,1 —2H2)prop—2-yn-1 -yI 4—methylbenzenesulfonate D D CH3 240/ \ HC ”8“ o 0 To a solution of (1,1-2H2)prop—2-yn—1-ol (3.40 9, prepared according to Fowler et al., Nucl. Med. Biol. 2001, 28 (7): 779 - 785, separation from residual ethanol was accomplished by fractional lation) in dichloromethane (250 mL) pyridine (7 mL) was added, and the resulting mixture was cooled to 0°C. Tosyl anhydride (21.0 g, 1.1 eq) was added to the mixture and the mixture was allowed to stir for 30 min, the cooling bath was removed and ng was continued for 1.5 h. The mixture was concentrated in vacuo and the residue was ed by column chromatography on silica gel (EtOAc in hexane 2.5% —> 25 %) to give the target compound in approx. 90 % puritiy (9.39 g, 68 % yield). 1H NMR (300 MHz, CDCls) 5 ppm 2.47 (m app 3, 4 H), 7.36 (d, 2 H), 7.83 (d, 2 H).

MS (ESI): [M + H]+ = 213.

Intermediate 1B: (3aS,8aR)—3,3a,8,8a-tetrahydroindeno[1,2—d][1,2,3]oxathiazole 2,2— dioxide To a solution of commercially ble (-)-(1S,2R)—cis—1-aminoindan—2—ol (12.8 g, 86 mmol) in dichloromethane (200 mL) triethylamine (29.9 mL, 214 mmol) was added, and the resulting e was cooled to -65"C by means of acetone/dry ice. A solution of sulfuryl chloride (8.27 mL, 103 mmol) in dichloromethane (250 mL) was added slowly (approx. 1 drop / sec) whilst maintaining temperature at -65°C. Upon complete addition, the cooling bath was removed and the mixture was allowed to warm up to room temperature. Stirring at room temperature was continued for 24 h. The e was washed twice with 2 N hydrochloric acid (200 mL each); the combined aqueous layers were extracted with dichloromethane (200 mL). The combined c layers were dried over sodium sulfate and evaporated. The crude residue was purified by column chromatography on silica gel (EtOAc in hexane 0 % —> 100 °/o), followed by trituration in hexane, gave an approx. 90 % pure t (5.6 g, 28 °/o yield). Repeated chromatography as described d a highly pure product. 1H NMR (300 MHz, de-DMSO) 5 ppm 3.19 (CI, 1H), 3.35 (dd, 1H), 5.29 (1, 1H), 5.52 (td, 1H), 7.14 - 7.44 (m, 4H), 8.32 (d, 1H).

MS (ESI): [M - H]' = 210.

Pre aration of com ounds accordin to the invention Example 1: (3aS,8aR)—3—[(1,1-2H2)prop—2-yn—1—yl]-3,3a,8,8a—tetrahydroindeno[1,2- d][1,2,3]oxathiazole 2,2-dioxide To a solution of Intermediate 1B (800 mg, 3,79 mmol) in DMF (30 mL) Intermediate 1A (1.29 g, 6.06 mmol) was added, followed by potassium carbonate (325 mesh, 2.09 g, .1 mmol), and sodium iodide (63 mg, 0.38 mmol). The resulting mixture was stirred at room ature for 48 h, and then partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate and ated. The residue was subjected to column chromatography on silica gel (EtOAc in hexane 0 % —> 100 %) to give the desired product, partly in crystalline form, in a combined yield of 77 % (795 mg). 1H NMR (400 MHz, CDCls) 5 ppm 2.53 (s, 1 H), 3.48 (d, 2 l ), 5.27 (d, 2 H), 5.53 - 5.60 (m, 1 H), 7.28-7.41 (m, 3 H), 7.49 (d, 1 H).

MS (ESI): [M + H]+ = 252. e 2: )fluoro—N—[(1,1—2H2)prop—2—yny|]indanamine Hill-n “7%CH D D To a solution of Example 1 (430 mg, 1.71 mmol) in a mixture of DMF (2.5 mL) and tert- butanol (25 mL) m fluoride (1.17 g, 7.70 mmol) was added, and the resulting e was stirred at room temperature for 60 h. All volatiles were then removed in vacuo, followed by on of 4 N hydrochloric acid (15 mL) and ethanol (15 mL) to the residue. The resulting mixture was stirred at 80 °C for 1.5 h, allowed to cool to room temperature, and then partitioned between ethyl acetate and saturated aqueous sodium carbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and lly evaporated (product is somewhat volatile). The residue was purified by column chromatography on silica gel (EtOAc in hexane 0% —> 40%) to give the desired product (241 mg, 74 % yield). lighly pure material (130 mg) was obtained by short-path lation of an aliquot (195 mg) using a Kugelrohr distillation apparatus (136 °C / 03 mbar) to give a colourless, crystalline solid upon cooling to room temperature.

A sample of the material was submitted to X—ray crystallography analysis confirming the assigned absolute stereochemistry. 1H-NMR (400MHz, CHLOROFORM-d) 5 ppm = 2.30 (s, 1H), 3.00 - 3.16 (m, 1H), 3.34 — 3.50 (m, 1H), 4.51 (dd, 1H), 5.08 — 5.27 (m, 1H), 7.22 - 7.39 (m, 4H).

MS (c1): [M + Hr = 192.

[G]D (c = 1.00, CHClg) = +49.3° Example 3: (1 S,2S)—2—[18F]fluoro—N-[(1,1—2H2)prop-2—ynyl]indan—1-amine IIIIl-rl Aqueous [18F]Fluoride (21.5 GBq) was trapped on a Sep-Pak light QMA cartridge (Waters) (activated with 5 mL 0.5M K2C03 solution, 10 mL water and 10mL air) and eluted with 2 mL K222/K2C03-solution (5 mg K222 in 0.95 mL acetonitrile, 1 mg K2C03 in 0.05 mL water) into the reactor. The solventwas removed by heating at 80°C for 3 min (N2 stream and vacuum) and at 120 °C for onal 3 min (vacuum). ous acetonitrile (1 mL) was added and evaporated as before. A solution of precursor example 1 (5 mg) in 500 pL anhydrous dimethyl sulfoxide (DMSO) was added. After heating the reaction mixture at 130 °C for 5 min additional 0.5 mL 1M HCl were added and the mixture was heated for 10 min at 100°C. The crude on mixture was then cooled down to room temperature and diluted with 4 mL mobile phase and purified by preparative HPLC: Synergi 4 p Hydro-RP 80A; 250 x 10.00 mm 4 micron; isocratic, 85% water (0.1% TFA), 15% acetonitrile (0.1%TFA), flow: 4 ; tR~18 min. The collected HPLC fraction was diluted with 40 mL water and immobilized on a Sep-Pak C18 plus cartridge (Waters), which was washed with 5 mL water and eluted with 1 mL ethanol to deliver the 4.0 GBq of the 18F labelled product (28 % rc. yield, corrected for decay; >99% HPLC) in 1000 pl ethanol in a overall synthesis time of ~70 min. The desired 18F ed t of example 3 (tR=2.26 min) was analyzed using analytical HPLC: ACE3-C18 50 mm x 4,6 mm; solvent gradient: start 5 % acetonitrile — 95 % acetonitrile in 0.1% trifluoroacetic acid in 7 min., flow: 2 mL/min and confirmed by co-injection with the corresponding non-radioactive 19F-fluoro-standard of example 2 on the analytical HPLC (tR=2.20 min).

Exam les demonstratin the su t of the com ounds accordin to the Specificity Binding of the [18F]rasagiline (compound of formula F) was igated on human brain ns from normal subjects using a standard protocol.

IIIIl-I'I t\///CH In brief, whole brain hemispheres were cut at a 100 pm thickness in a Cryocut (Leica, Germany), thaw mounted onto ne glass slides and kept at -25°C before use.

Thereafter, the slides containing the regions of interest (e.g. hippocampus, thalamus) were removed and brought to room temperature. The sections were incubated with 0.2 MBq/mL [18F] compound F in 50 mM TRIS / 0.1% BSA (pH 7.4) with salts (120 mM NaCI, 5 mM KCI, 1 mM CaClz, 1 mM MgCI2) for 90 min at room temperature and washed three times for 5 min each in 50 mM TRIS (pH 7.4). The sections were dipped once into ice cold distilled water, dried at room temperature and exposed to Phosphorlmager plates (FUJI BAS 5000) overnight.

For detection of the specificity of the signals an excess (10 pM) of deprenyl, rasagiline (both for MAO-B) and pirlindole (for MAO-A), respectively, was used together with the 18F labelled rasagiline (compound F).

Autoradiography using [18F]rasagiline on human brain slices from a healthy t resulted in.the detection of a high signal intensity in the globus pallidus, the putamen, caudate, thalamus and hippocampus, regions with known MAO-B activity. The signals could not be blocked by an excess of dole, a reversible MAO-A inhibitor (Pharmacol. Res. 1997, 36: 23-33) in the incubation solution. An excess of deprenyl or line, respectively, added to the incubation solution completely blocked the [18F]rasagiline (compound F) signal. These data show that [18F]rasagiline is a ligand specifically interacting with MAO-B. In summary, [18F]rasagiline (compound F) labelled ically brain structures known to express MAO-B such as the hippocampus, caudate, putamen and thalamus.

These signals were blocked by an excess of compounds specific for MAO-B but not by dole, a MAO-A ic compound.

Uptake and ut Thus, demonstrating the specificity of the signals, [18F]rasagiline (compound F) has been tested in a cynomolgus monkey. One monkey weighing 6.3 kg was injected iv. with 163 MBq [18F]rasagiline und F) under sevofluorane anaesthesia. In a HRRT camera (Siemens Molecular Imaging) brain time activity curves (TAC) have been monitored and the standard uptake values (SUV) as shown in Fig. 1 were calculated. The initial brain uptake was ca. 280 °/oSUV within whole brain (Fig. 1, left panel) and ca. 400 %SUV when a striatal (caudate and putamen) and thalamic region of interest (ROI) were investigated (Fig. 1, right panel). The TACs for striatum and thalamus ed at a comparable value, as did the TACs for cortex and cerebellum but the latter one at a lower value (Fig. 1, right panel).

In a second step, [13F]rasagiline has been synthesized as the di-deuterated version [13F],(2H2)rasagiline (compound 1).

IIIII‘I'I Two cynomolgus monkeys weighting 5.25 and 6.2 kg, respectively were investigated.

They were injected i.v. under sevofluorane anaesthesia with 168 MBq and 174 MBq [18F],(2H2)rasagiline (1), respectively. In a HRRT camera (Siemens Molecular imaging) brain time activity curves (TAC) have been monitored and standard uptake values (SUV) as shown in Fig. 2 were calculated. It was found, that the initial uptake of [13F],(2H2)rasagiline (1) in whole brain was comparable to that of [18F]rasagiline und F). The same was observed for the brain regions analyzed, i.e. striatum, thalamus, cortex and cerebellumHowever, the TACs had now a shape characterized by a peak immediately after injection and ation until a plateau is reached (steady state), as it is usually observed for reversible ligands (Fig. 2). [18F]rasagiline PET images from a ic plane of the monkey brain, covering um and thalamus as regions with high MAO B ty, demonstrated a high and specific signal in these regions whereas the signal in cerebral cortical structures was low. When using [18F],(2H2)rasagiline for detection of MAO B ty in brain regions with high MAO B activity — striatum and thalamus — the signal declined to a lower value. It was still prominent and well distinguishable from the surprising low signal in cerebral cortical areas being in line with the %SUV TACs at steady state.

To demonstrate specificity of [18F],(2H2)rasagiline (1) one monkey was pre-treated with 0.5 mg/kg (L)-deprenyl, a known irreversible inhibitor of MAO-B. This eatment led to a strong se in uptake by 40 to 47%, respectively, in the investigated ROls (Striatum 45%, Thalamus 47%, Cerebellum 46% and cortex 40%) demonstrating specificity of the [18F],(2H2)rasagiline (Fig. 3).

Metabolic profile In addition, the blood radioactivity profiles have been monitored over time using radio— HPLC measurements and were decay corrected (d.c.) (Fig. 4 and 5). For [18F]rasagiline (compound F) eight 18F labelled metabolites have been observed in addition to the parent compound in plasma over the time period of the investigation (Fig. 4, Table 1).

Unexpectedly, there was a strong ion in the number of metabolites from eight to two when the blood radioactivity profiles of [18F],(2H2)rasagiline (1) were red (Fig.

, Table 2).

In agreement with this, the metabolite corrected blood input curve from the PET experiments with [18F],(2H2)rasagiline (1) showed an increased blood radioactivity over time when the curve was ed to the respective curve of the non-deuterated compound (Fig. 6).

Reduced trapping in steady state phase A particularly important improvement of MAO-B imaging is the surprising technical effect that a decrease in signal intensity from [18F]rasagiline (compound F) towards [13F],(2H2)rasagi|ine (1) is between 2.4 -3 times in the brain regions investigated during the steady state phase (see Fig. 7). The d trapping rate of deuterated [13F],(2H2)rasagiline (compound 1) compared to [18F] rasagiline (compound F) enables an improved quantification of MAO-B activity and avoids blood flow limitation of delivery of the , since it is known that a high trapping rate is sible for an underestimation of the MAO-B signal in regions with high MAO-B ty (Fowler et al.

Mol. Imaging Biol. 2005, 7: 377-387).

The effect strongly exceeds effects reported for compounds from the prior art and hence could not be expected by the person skilled in the art.

From studies using [“C]deprenyl (compound H) it is known that the MAO-B signal is underestimated in regions with high MAO-B ty due to high trapping rate that is similarto or exceeds delivery (Fowler et al. J Nucl Med 1995; 36: 1255). 2012/054917 Putting deuteron atoms in place at [“C]deprenyl (compound H) yielding [“C],(2H2)deprenyl (compound G) has been reported to result in a reduced ng rate.

“CH3 11CH3 This leads to a more le quantification of the signal. But the positive effect of deuteration on the decrease in signal intensity for [“C],(2H2)deprenyl (compound G) is only 1.2 — 20-fold being observed in healthy baboon and human brain regions (e.g. striatum, thalamus, cortex, Fowler et al. J. Neurochem 1988, 51: 1524-1534; J. Nucl.

Med. 1995, 36: 1255-1262; Mol. Imaging Biol. 2005, 7: 377-387).

Thus, the entioned ed ratio of signal intensity of [18F]rasagiline (compound F) to [18F],(2H2)rasagiline (1) is surprisingly higher (2.4 to 3) than the published ratio of signal intensity of [“C]deprenyl (compound H) to [“C],(2H2)deprenyl (compound G) (~12 to 2.0) (Fig. 8).

More specifically, the unexpected observation is that regions with high MAO-B expression had a more pronounced decrease in signal intensity when compared to the effect that was expected from data published for [“C],(2H2)deprenyl (compound G) and prenyl (compound H).

In striatum the decrease was 2.9 times for [13E 2H2]rasagiline (1) compared to only 1.7 times published for [“C],(2H2)deprenyl (compound G). rmore, in thalamus the se was 2.7 times for [13F],(2H2)rasagiline (1) compared to only 1.3 times published for [“C],(2H2)deprenyl (compound G).

Another unexpected finding was in the cerebellum, an expected reference region with very low MAO-B activity. Here the decrease in signal intensity was 3.0 and thus, being twice as much as published for [“C],(2H2)deprenyl levelling at 1.5. ically, its low signal in the reference region cerebellum renders the compounds of the invention as superior PET imaging agents leading to increased ratios of target regions to cerebellum as a reference region.

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Claims (26)

What we claim is:

1. A compound of formula I (R1)(Q)(R2) CH wherein (R1)(Q)(R2) is selected from the group consisting of (O)(bond)(S(O)2), ([18F]fluoro)(blank)(S(O)2(O-)(X+)), (F)(blank)(S(O)2(O-)(X+)), ([18F]fluoro)(blank)(H), and (F)(blank)(H); X+ is selected from the group consisting of Li+, Na+, K+, Cs+, and/or Rb+; bond means that the atoms or atom groups adjacent to the bond share at least one pair of ons and thus are ally bonded to each other; blank means that there is neither a chemical bond nor an atom or an atom group connecting R1 and R2. including enantiomers and diastereoisomers as well as mixtures thereof of said compound and any pharmaceutically acceptable salt or complex thereof.

2. A compound of claim 1, characterized in that the nd is selected from a compound of formula Ia 18F CH including enantiomers and diastereoisomers as well as mixtures thereof of said compound and any pharmaceutically acceptable salt or complex thereof.

3. A compound of claim 2, characterized in that the compound is (1S,2S)[18F]fluoro-N-[(1,1-2H2)propynyl]indanamine D D including any pharmaceutically acceptable salt or complex thereof.

4. A compound of claim 1, terized in that the compound is selected from a nd of a Ib F CH including enantiomers and diastereoisomers as well as mixtures thereof of said compound and any pharmaceutically acceptable salt or complex thereof.

5. A compound of claim 4, characterized in that the compound is (1S,2S)fluoro-N-[(1,1-2H2)propynyl]indanamine H CH D D ing any pharmaceutically acceptable salt or complex thereof.

6. A compound of claim 1, characterized in that the compound is ed from a compound of formula Ic O S O including enantiomers and diastereoisomers as well as mixtures thereof of said compound and any pharmaceutically acceptable salt or complex thereof.

7. A compound of claim 6, characterized in that the compound is (3aS,8aR)[(1,1-2H2)propynyl]-3,3a,8,8a-tetrahydroindeno[1,2d][1,2,3] oxathiazole 2,2-dioxide O S O H CH H D including any pharmaceutically able salt or complex thereof.

8. A compound of claim 1, characterized in that the compound is selected from a compound of formula Id O O S O CH wherein X+ is ed from the group Li+, Na+, K+, Cs+, and/or Rb+; including enantiomers and reoisomers as well as mixtures thereof of said compound and any pharmaceutically acceptable salt or complex thereof.

9. A compound of claim 8, characterized in that the compound is potassium N-[(1S,2S)[18F]fluoroindanyl]-N-[(1,1-2H2)propynyl]sulfamate 18F O O CH including any pharmaceutically acceptable salt or complex thereof.

10. A nd of claim 1, characterized in that the compound is ed from a compound of formula Ie X+ –O O F CH S O wherein X+ is selected from the group Li+, Na+, K+, Cs+, and/or Rb+; including enantiomers and diastereoisomers as well as mixtures thereof of said compound and any pharmaceutically acceptable salt or complex thereof.

11. A compound of claim 10, characterized in that the compound is caesium N-[(1S,2S)fluoroindanyl]-N-[(1,1-2H2)propynyl]sulfamate F –O O CH ing any pharmaceutically acceptable salt or complex thereof.

12. A compound of claims 2 or 3 as a diagnostic compound for PET g.

13. A diagnostic composition comprising a compound of claims 2 or 3.

14. A compound of claims 2 or 3 as a diagnostic compound for PET imaging of CNS diseases.

15. A diagnostic composition comprising a compound of claims 2 or 3 for PET imaging of CNS diseases.

16. A compound or a composition according to claims 12 to 15 for g of mer’s disease.

17. Method for the synthesis of a compound of according to formula I (R1)(Q)(R2) CH wherein (R1)(Q)(R2) is selected from the group consisting of (O)(bond)(S(O)2), ([18F]fluoro)(blank)(S(O)2(O-)(X+)), (F)(blank)(S(O)2(O-)(X+)), ([18F]fluoro)(blank)(H), and ank)(H); X+ is selected from the group consisting of Li+, Na+, K+, Cs+, and/or Rb+; bond means that the atoms or atom groups adjacent to the bond share at least one pair of electrons and thus are chemically bonded to each other; blank means that there is neither a chemical bond nor an atom or an atom group connecting R1 and R2; the method comprising the steps - converting a compound of formula III O S O into a compound of formula IV O S O - optionally reacting obtained compound of a IV with a 18F- or 19F-fluorination agent, thereby obtaining a compound of formula Id or Ie, O X+ O O O 18F CH 19 S O F S O CH N N D D D D Id Ie wherein X+ is selected from the group consisting of Li+, Na+, K+, Cs+, and/or Rb+, - optionally reacting obtained compound of formula Ie or Id with acid, thereby ing a compound of formula Ia or Ib 18F 19 CH F CH H H N N D D D D Ia Ib - optionally converting obtained compound Ia, Ib, Id or Ie into a suitable salt of inorganic or c bases, hydrates, complexes, and/or solvates thereof.

18. A kit comprising at least one sealed container comprising a compound or a composition according to claims 1-16.

19. The use of a compound according to any one of claims 1 to 11 in the cture of a diagnostic composition for PET imaging.

20. The use ing to claim 19, which is for PET imaging of CNS diseases.

21. The use according to claim 19 or 20 for imaging of Alzheimer’s disease.

22. A compound according to claim 1, substantially as herein described or exemplified.

23. A diagnostic composition according to claim 15, substantially as herein bed or exemplified.

24. A method according to claim 17, substantially as herein described or exemplified.

25. A kit according to claim 18, substantially as herein described or ified.

26. A use according to claim 19, substantially as herein described or exemplified.