NZ617331B2

NZ617331B2 - Novel precursors of glutamate derivatives

Info

Publication number: NZ617331B2
Application number: NZ617331A
Authority: NZ
Inventors: Mathias Berndt; Matthias Friebe; Michael Harre; Christina Hultsch; Byoung Se Lee; Filip Novak; Sang Don Park; Heribert Schmittwillich; Chi Dae Yoon
Original assignee: Piramal Imaging Sa
Priority date: 2011-05-03
Filing date: 2012-04-30
Publication date: 2015-11-03

Abstract

Disclosed are precursors suitable for F radiolabeling of glutamate derivatives, methods for preparing the compounds, and compositions and kits comprising the compounds. Also disclosed are compositions and methods for F radiolabeling of glutamate derivatives wherein the obtained F radiolabeled glutamate derivatives are suitable for diagnostic imaging by Positron Emission Tomography (PET) of proliferative diseases e.g. tumor in mammals. ate derivatives are suitable for diagnostic imaging by Positron Emission Tomography (PET) of proliferative diseases e.g. tumor in mammals.

Description

Novel precursors of Glutamate derivatives Field of Invention This invention relates to novel sors le for 18F radiolabeling of glutamate derivatives, methods for preparing such compounds and their intermediates, compositions comprising such compounds, kits comprising such compounds or compositions and methods for 18F radiolabeling of glutamate derivatives wherein the obtained 18F radiolabeled glutamate derivatives are suitable for diagnostic imaging by Positron Emission Tomography (PET) of erative es e.g. tumor in s.

Background The early diagnosis of malignant tumor diseases plays an ant role in the survival prognosis of a tumor patient. For this diagnosis, non-invasive stic imaging methods are an important aid. In the last years, in particular the PET (Positron Emission Tomography) technology has been found to be particularly useful. The sensitivity and specificity of the PET logy depends essentially on the -giving substance (tracer) used and on its distribution in the body. In the hunt for suitable traces, one tries to make use of certain properties of tumors which differentiate tumor tissue from healthy surrounding tissue. The preferred cial isotope used for PET applications is 18F. Owing to the short half-life of less than 2 hours, 18F is ularly ing when it comes to the preparation of suitable tracers. This isotope does not allow complicated long synthesis routes and purification procedures, since otherwise a considerable amount of the radioactivity of the e will already have decayed before the tracer can be used for diagnosis. Therefore, often it is not possible to apply established synthesis routes for non-radioactive nations to the synthesis of 18F tracers. Furthermore, the high specific activity of 18F (about 80 GBq/nmol) leads to very low substance amounts of [18F]fluoride for the tracer synthesis, which in turn es an extreme excess of precursor, making the result of a radio synthesis strategy based on a non-radioactive fluorination reaction unpredictable.

FDG ([18F]—2-Eluorogeoxyglucose)-PET is a widely accepted and frequently used auxiliary in the diagnosis and further clinical monitoring of tumor disorders. Malignant tumors compete with the host organism for glucose as nutrient supply rg O., Uber den Stoffwechsel der Carcinomzelle [The metabolism of the carcinoma cell], Biochem.Zeitschrift 1924; 152: 309-339; KellofG., Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development, Clin. Cancer Res. 2005; 11(8): 2785-2807).

Compared to the surrounding cells of the normal tissue, tumor cells usually have an sed glucose metabolism. This is exploited when using deoxyglucose (FDG), a glucose derivative which is increasingly transported into the cells, where, however, it is metabolically captured as FDG phate after phosphorylation ("Warburg effect").

Accordingly, 18F-labeled FDG is an effective tracer for detecting tumor disorders in patients using the PET technology. In the hunt for novel PET tracers, recently, amino acids have been employed increasingly for 18F PET imaging (for example (review): Eur. J. Nucl. Med.

Mol. Imaging May 2002; 29(5): 681-90). Here, some of the 18F-labeled amino acids are suitable for measuring the rate of protein synthesis, but most other derivatives are suitable for measuring the direct cellular uptake in the tumor. Known 18F-labeled amino acids are derived, for e, from tyrosine amino acids, phenylalanine amino acids, proline amino acids, asparagine amino acids and unnatural amino acids (for example J. Nucl. Med. 1991; 32: 1338-1346, J. Nucl. Med. 1996; 37: 5, J. Nucl. Med. 2001; 42: 4 and J.

Nucl. Med. 1999; 40: 331-338).

Recently, the use and the sis of 18F/19F-labeled glutamic acid derivatives and glutamine derivatives has been published (WO2008052788, WO2009141091). Compounds with very promising preclinical results (WO2008052788, J. Med. Chem. 2011; (54):406—410, J Nucl Med. 2010; 51 ement 2):1535) were tested in first al s. For [18F] -glutamic acid good tumor uptake was found. However, some defluorination was detected which negatively influenced the tumor-background-ratio. (J Nucl Med. 2010; 51 (Supplement 2):118). Superior results were obtained applying (S)—4-(3-[18F]Fluoropropyl)—L- glutamic acid in first clinical studies. Very good results were found in the ion of lung cancer (Koglin et al., Abstract Nr. 412, SNM 2011, San Antonio; Baek et al., Abstract Nr. 195, SNM 2011, San Antonio).

Common leaving groups for labeling in alkyl positions bed in the literature are sulfonates such as mesylate, tosylate, and triflate or halides (Ernst Schering Res Found Workshop. 2007; (62):15-50 and Eur. J. Org. Chem. 2008, 2853—2873).

Novel leaving groups with different scopes have been published. Lu et al. describe the use of leaving groups which already contain the phase er st for the introduction of the [18F]fluoride (Lu et al. J. Org. Chem. 2009; (74):5290—5296). These leaving groups contain an arylsulfonate and a chelating unit which is attached to the aryl ring via an ether ring.

Furthermore, the use of special leaving groups which support the removal of the precursor in a purification step after the radiolabeling was reported (WO2011006610). The leaving groups described are sulfonates containing a lipophilic part to allow a simple purification.

For the synthesis of 4-(3-[18F]Fluoropropyl)—L-glutamic acid different precursors have been described.

In W02008052788 and W02009141091, the precursor is a ation of known amino and carboxyl protecting groups and g groups such as of Chloro, Bromo, sulfonate tives such as Tosyloxy resulting into a suitable 18F radiolabeling precursor in oily form.

W02010000409 refers to the use of novel perfluorinated precursors, its 18F-radiolabeling and the purification of the resulting compound. These methods were also applied for the manufacture of 4-(3-[18F]Fluoropropyl)—L-glutamic acid.

However, the synthesis of the compound remains challenging. One important factor in the production of the radiotracer is a precursor suitable for 18F radiolabeling. Due to the presence of different functional groups (carboxylic group, amino group) the introduction of protecting groups is necessary for ting the abeling without loss of functional groups. In addition, the presence of a leaving group is required to enable the philic uction of the 18F-label.

Until now, no solid precursor for the synthesis of 4-(3-[18F]Fluoropropyl)—L-glutamic acid has been described. m to be solved by the invention and its solution For a routine clinical use of a 4-(3-[18F]Fluoropropyl)—L-glutamic acid, a reliable and robust manufacturing process is needed, that is compliant with Good Manufacturing Practice requirements (GMP) and provides a stable injectable solution (isotonic, appropriate pH) of the radiotracer with a low content of impurities. ln face of the short half-live of 18F (110 min), the process has to provide the radiolabeled tracer in high radiochemical yield within short synthesis time rably less than 60 min).

Manufacturing of the radiolabeled tracer is usually performed on automated systems. For routine applications pre-manufactured Kits containing (inter alia) the required amount of sor are frequently used. In general, the reagents used for the manufacture of the radiolabeled tracer — including the precursor — need sufficient stability for shipment and storage.

Furthermore, the physicochemical nature of the precursor is also very important: oily or resinous precursors cause technical ms during filling (e.g. into Kits). Either the weighing of an te precursor amount is tedious and expensive or the weighed amount is not exact. The latter can cause synthetic problems or result in higher impurity content. It is therefore preferable to have solid precursors.

The glutamic acid derivatives of the present invention of a la and Ila, as well as lb and llb have two stereo centers in the 2 and 4 positions. A method for manufacturing these compounds has to ensure high optical purity. 18F labeled ic acid derivatives of formula Illa-F18 and lVa-F18, as well as lllb-F18 and lVb-F18 have also two stereo centers in the 2 and 4 positions. A method for manufacturing these compounds has to assure, that the labeling reaction conditions do not lead to a significant degree of epimerization at one or both stereo centers.

Forthe manufacture of (S)(3-[18F]Fluoropropyl)—L-glutamic acid or for (R)—4-(3- [18F]Fluoropropyl)—L-glutamic acid it is therefore desirable to have a precursor that is: 1. stable 2. solid and 3. labeled under sufficiently mild conditions, preventing the loss of stereochemical integrity.

The present invention solves the above mentioned problems by providing stable (e.g. storage at 2 -20°C), optically pure, solid and iently reactive precursors for the manufacturing of fluorine labeled glutamate derivatives.

Remotely controlled synthesizers for 18F labeling are adaptable to these precursors to allow a GMP compliant manufacturing of the radio .

Summam of the Invention For the synthesis of (S)(3-[18F]Fluoropropyl)—L-glutamic acid new stable and solid labeling precursors of a la have been invented. The problems mentioned above have been solved by the uction of a l combination of the protecting groups and the leaving groups. Especially, the use of a trityl protecting group at the amino function in combination with an ic ring containing leaving group resulted in solid nds. The resulting precursors can be easily 18F-radiolabeled and deprotected to obtain (S)(3- [18F]Fluoropropyl)—L-glutamic acid (scheme 1a). The new precursors of Formula lb bearing the substituent at 0-4 in “R” ation can be used for the manufacturing of (R)—4-(3- [18F]Fluoropropyl)—L-glutamic acid (scheme 1b). 2012/057884 o 0 o o “30 W CH3 H30 CH3 H3c+o 0+CH3_> H3c+o_> _ O+CH3 H3C HN CH3 H3O NH2*HC| CH3 J/ \Trt HO Formula Ila Formula la Formula lVa-F18 Formula llla-F18 Scheme 1a: Synthesis of (S)(3-[18F]FIuoropropyI)—L-glutamic acid (lVa-F18) from compounds of Formula la.

O O “30 W CH3 H3C+O >—> H C“3+0O O.83CH $430 3 HN CH3 H3O NH2*HC| CH3 ‘Trt HO Formula Ilb O 0 H30 CH3 H30 0 O+CH3 H3C HN\ CH3 Formula lb 0 O O 0 H30 CH3 HO 0“ H30 0 O+CH3 NH2 <— H3C HN\ CH3 ‘— Trt 18': Formula lVb-F18 Formula lllb-F18 Scheme 1b: Synthesis of (R)—4-(3-[18F]Fluoropropyl)—L-glutamic acid (lVb-F18) from compounds of Formula lb.

The present ion provides furthermore methods for manufacturing of radiolabeled compounds of Formula lV-F18, lVa-F18 and lVb-F18 using herein disclosed compounds of Formula I, la and lb.

Detailed ption of the Invention In a first aspect, the invention is directed to compounds of the formula I (precursors), Formula | O O H3C CH3 H3C o O+CH3 H3C HN CH3 0o ,o A’s“ wherein R1 is triphenylmethyl (Trityl), A is selected from the group: a) Monocyclic aryl, b) Bicyclic aryl, C) Biaryl, d) Monocyclic heteroaryl, and e) Bicyclic heteroaryl optionally, A is bearing one or more substituents selected from the group comprising: a) n, b) Nitro, c) Alkyl, d) Trifluoromethyl, and e) Z, whereinZis O 0 H30 CH3 H30 0 O+CH3 H3C HN'R1 CH3 O\\S,O #’ “o R1 is triphenylmethyl l), # indicates the position of the bond to A, and single isomers, tautomers, diastereomers, omers, stereoisomers, mixtures thereof, and suitable salts f.

Preferred features: Preferably, A is selected from the group: a) phenyl, b) biphenyl, c) naphthyl, and d) inyl, optionally, A is bearing 1 to 4 substituents selected from the group comprising: a) Halogen, b) Nitro, C) 01-03 alkyl, d) Trifluoromethyl, and e) Z.

More preferably, A is selected from the group: a) phenyl, b) biphenyl, c) naphthyl, and d) inyl, optionally, A is bearing 1 to 3 substituents selected from the group comprising: a) Halogen, b) Nitro, c) Trifluoromethyl, and d) Z.

Even more preferably, A is selected from the group: a) phenyl, b) yl, c) naphthyl, and d) quinolinyl, optionally, A is g 1 to 3 substituents selected from the group comprising: a) Chloro, b) Nitro, c) Trifluoromethyl, and d) Z.

Even more preferably, A is selected from the group: a) phenyl, b) biphenyl, c) naphthyl, and d) quinolinyl, optionally, A is bearing 1 to 3 substituents selected from the group comprising: a) Chloro, b) Nitro, and c) Trifluoromethyl.

Even more preferably, A is selected from the group: a) phenyl, b) biphenyl, c) naphthyl, and d) quinolinyl, optionally, A is bearing 1 to 3 tuents selected from Chloro, and optionally, A is bearing 1 tuent selected from the group consisting of: a) Nitro, and b) Trifluoromethyl.

In a preferred embodiment A is phenyl, optionally substituted as described above.

In r preferred embodiment A is biphenyl, optionally substituted as described above.

In another preferred embodiment A is naphthyl, optionally substituted as described above.

In another preferred embodiment A is quinolinyl, optionally substituted as described above.

In a more preferred embodiment A is nitrophenyl.

In another more red ment A is biphenyl.

In another more preferred embodiment A is quinolinyl.

In another more preferred embodiment A is yl-Z.

In a more preferred embodiment A is nitro-(trifluoromethy)phenyl.

In a more preferred embodiment A is yl.

In a more preferred embodiment A is trichlorophenyl.

In a more red embodiment A is nitronaphthyl.

In an even more preferred embodiment A is In another even more preferred embodiment A is In another even more preferred embodiment A is In another even more preferred embodiment A is In another even more preferred embodiment A is # o 2‘ In r even more preferred ment A is ?No2 In another even more preferred embodiment A is In another even more preferred embodiment A is In another even more preferred embodiment A is <3CI In another even more preferred embodiment A is N02 In another even more preferred embodiment A is # indicates the position of the bond to A in formula I.

Halogen is , Fluoro, lodo or Bromo. Preferably, halogen is Chloro.

Alkyl is a branched or unbranched C1-Ce Alkyl. Preferably, alkyl is methyl, ethyl or propyl.

In a preferred embodiment formula I relates to compounds with (28,4S)-configuration (compound of formula la) with diastereomeric and enantiomeric purity of >80%, preferably >90%, more preferably 95% and even more preferably >98%. 0 0 H30 CH3 H30 0 O+CH3 H3C = f HN CH3 O» ,o A’s“ o la wherein A and R1 are d as for formula I above.

In another preferred embodiment formula I relates to compounds with (28,4R)—configuration (compound of formula lb) with diastereomeric and enantiomeric purity of >80%, ably >90%, more preferably 95% and even more preferably >98%. 0 0 H30 CH3 H30 0 O+CH3 H3C HN‘ CH 0» ,o A’s“ 0 lb wherein A and R1 are defined as for formula I above.

A red compound of Formula I is di-tert-butyl (4S)(3-{[(4- nitrophenyl)sulfonyl]oxy}propyl)-N-trityl-L-glutamate A preferred compound of Formula I is di-tert-butyl (4S)—4-(3-{[(3- nitropheny|)su|fony|]oxy}propy|)-N-trity|-L-g|utamate H3Cj\H3 O 0 ﬂow H30 0 0 CH3 f HN O o=s=o O O A preferred nd of Formula I is di-tert-butyl (4S){3-[(bipheny|—4- ylsu|fony|)oxy]propy|}-N-trityI-L-gIutamate 0 O H ($033 3 J<CH3 A preferred compound of a I is di-tert-butyl (4S){3-[(2-naphthy|sulfony|)oxy]propy|}- N-trityI-L-glutamate A preferred compound of Formula I is di-tert-butyl (4S){3-[(1-naphthy|su|fony|)oxy]propy|}- N-trityI-L-glutamate A preferred compound of Formula I is di-tert-butyl -{3-[(quino|in-8— ylsu|fony|)oxy]propy|}-N-trityI-L-gIutamate CH O 0 H3CS\3 kCHs H3C o 0 CH3 f HN O O=S=O O O A red compound of Formula I is di-tert-butyl (4S)(3-{[(2,4,6- trich|oropheny|)su|fony|]oxy}propy|)-N-trity|—L-g|utamate A preferred compound of Formula I is tetra-tert-butyl (28,4S,2'S,4'S)—2,2'-[bipheny|—4,4'- diylbis(suIfonyloxypropane-3,1-diyl)]bis[4-(trity|amino)pentanedioate] A preferred compound of Formula I is t-butyl (4S)(3-{[(7-nitro naphthyl)su|fony|]oxy}propy|)-N-trity|—L-g|utamate wo 2012/150204 CH o 0 CH3 H30 3 CH3 0 CH3 A preferred compound of Formula I is di-tert-butyl (4S)[3-({[4-nitro (trifluoromethy|)pheny|]su|fony|}oxy)propyl]—N-trity|—L-gIutamate A red compound of Formula I is di-tert-butyl (4S)(3-{[(4- methylphenyl)su|fony|]oxy}propy|)-N-trity|-L-g|utamate.

CH O O w w H30 0 0 E CH3 A preferred compound of Formula I is t-butyl (4R)(3-{[(4- methylpheny|)su|fony|]oxy}propy|)-N-trity|-L-g|utamate.

A preferred compound of Formula I is di-tert-butyl (4R)—4-{3-[(2-naphthylsulfonyl)oxy]propyl}- N-trityl-L-glutamate CH o 0 CH3 The second aspect of the present invention is directed to compounds of Formula I, la or lb in the solid form. Preferably, the present invention is directed to the solid compounds of Formula I, la or lb as listed above.

Additionally the invention is directed to s for obtaining a crystalline form of compounds of formula I, la or lb. Crystallization s are well known to the person skilled in is the art.

In a preferred embodiment, the t invention is directed to crystalline compounds of Formula I, la or lb.

Preferably, the following nd is in a crystalline form Di-tert—butyl (4S)—4-{3-[(2- naphthylsulfonyl)oxy]propyl}-N-trityl-L-glutamate. 2012/057884 Preferably, the following compound is in a crystalline form Di-tert-butyl (4R)—4-{3-[(2- ylsulfonyl)oxy]propyl}-N-trityl-L-glutamate.

In a third aspect, the invention is directed to methods for obtaining nds of formula I.

Method for obtaining compounds of formula I The method for obtaining compounds of formula I is med by sulfonylation of the hydroxy group in Formula II with a suitable sulfonylhalide (preferably, sulfonylchloride) or anhydride with a suitable tuent A to form a compound of formula I as defined above.

The method for obtaining compounds of formula I comprises the step: - Sulfonylation of compound of Formula II with a sulfonylhalide rably, sulfonylchloride) or sulfonyl anhydride having both a suitable substituent A.

Formula II Formula | O O O O H3C CH3 H3C CH3 H3c+o O+CH3 —> H3c+o O+CH3 H3C HN‘ CH3 H3C HN‘ CH3 R1 R1 HO O“ ,o A ‘0\ wherein R1 is triphenylmethyl (Trityl), A is selected from the group: a) Monocyclic aryl, b) Bicyclic aryl, c) Biaryl, d) Monocyclic heteroaryl, and e) ic heteroaryl optionally, A is bearing one or more substituents selected from the group comprising: a) Halogen, b) Nitro, c) Alkyl, d) Trifluoromethyl, and e) Z, Z is o 0 H30 CH3 H3C+O O+CH3 H3C HN CH3 O» ,o #’S\\ R1 is triphenylmethyl (Trityl), # indicates the position of the bond to A.

In another embodiment, a bis-sulfonylhalide X-SOz-A—SOz-X is reacted with two molecules of compound of formula II to obtain a compound of formula I, wherein A is tuted with Z as describe above. X is halogen, preferably X is Chloro.

Method for obtaining compounds of formula la Preferably, the method is conducted by reacting compounds of formula Ila for obtaining compounds of formula la with (28,4S)-configuration - Sulfonylation of compound of Formula Ila with a sulfonylhalide (preferably, sulfonylchloride) or sulfonyl anhydride having both a suitable substituent A.

Formula Ila a la wherein A and R1 are defined above.

Method for obtainin com ounds of a lb Preferably, the method is ted by reacting compounds of formula llb for obtaining compounds of formula lb with (28,4R)—configuration - Sulfonylation of compound of a llb with a sulfonylhalide rably, sulfonylchloride) or sulfonyl anhydride having both a suitable substituent A.

Formula llb Formula lb 0 O O O H3C CH3 H3C CH3 H3C o O+CH3 —> H3C o O+CH3 H3C HN‘ CH3 H3C HN CH3 R R1 HO 00 ,o ‘0\ A wherein A and R1 are defined above.

In another preferred embodiment, the method is ted by reacting a mixture of compounds of formula Ila and Ilb for obtaining a mixture of compounds of formula la with (28,4S)-configuration and compounds of formula lb with (28,4R)—configuration that can be separated by methods known to the person skilled in the art (e.g. chromatography, llization) to obtain ed compounds of formula la and isolated compounds of formula lb Formula la 0 O H3C CH3 H3C o O+CH3 H3C = HN‘ CH3 Formula Ila/b J/ R1 0o ,o o 0 Also H3C CH3 0 H3C O O—éCH3 —> + H3C HN‘ CH3 R Formula lb HO 0 O H3C CH3 H3c+o O+CH3 H3C HN_ CH 0o ,o A ‘0\ wherein A and R1 are defined above.

The reagents, solvents and conditions which can be used for this sulfonylation are common and well-known to the skilled person in the field. (J. March, Advanced c Chemistry, 4th ed. 1992, John Wiley & Sons, pp 352ff).

The sulfonylation of compounds of formula II to compounds of formula I is med in a suitable inert solvent, in the presence of a suitable base, optionally in a microwave reactor in is performed at an elevated temperature, a temperature between -10 ° C case the reaction and 150 °C and at a pressure up to 5 bar.

Suitable inert solvents are amides such as N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidinone, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, or dioxane, halogenated hydrocarbons such as dichloromethane or chloroform, or others such as or acetonitrile.

Suitable bases are alkali carbonates, such as sodium carbonate or ium carbonate, alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, N,N-diisopropylethylamine, ne, ylmorpholine, N-methylpiperidine, or DBU (1,8- icyclo(5.4.0)—undecene).

Preferred inert ts are dichloromethane or tetrahydrofuran.

Preferred bases are triethylamine, N,N-diisopropylethylamine or pyridine.

The red features and embodiments disclosed for compounds of general formula I, la, lb, ll, Ila and llb are herein incorporated.

In a fourth aspect, the invention is directed to methods for obtaining compounds of formula Method for obtaining lV-F18: by direct labeling of compounds of formula I The direct method for obtaining compounds of formula lV-F18 comprises the steps - Reacting compound of Formula lwith a 18F-Fluorination agent to obtain compound of formula Ill-F18, and - Deprotecting the obtained compound of formula Ill-F18 for obtaining nd of formula lV-F18, compound of formula Ill-F18 is O 0 H30 CH3 H30 0 O+CH3 H3C HN ‘ CH3 18': a lll-F18 wherein R1 is triphenylmethyl (Trityl),and compound of formula lV-F18 is O O HO OH 18': Formula lV-F18 Optionally the method is followed by the purification of compound of Formula lV-F18 by solid- phase-extraction. Preferably solid-phase-extraction cartridges or columns are used.

Preferably, the direct method for obtaining nds of formula lVa-F18 ses the steps - Reacting compound of Formula la with a 18F-Fluorination agent to obtain compound of formula Illa-F18, and - Deprotecting the obtained compound of formula Illa-F18 for obtaining compound of formula lVa-F18, wherein compound of a 18 is O 0 Formula Illa-F18 R1 is triphenylmethyl (Trityl) and compound of formula lVa-F18 is O O HOWOH R. NH2 18': Formula lVa-F18 Optionally the method is followed by the purification of compound of Formula lVa-F18 by solid-phase-extraction. Preferably phase-extraction cartridges or columns are used.

The 18F-Fluorination agent are exemplified by but not limited to K18F, H18F, Rb18F, Cs18F, Na18F.

Optionally, the 18F-Fluorination agent comprises a chelating agent such as a cryptand (e.g.: 4,7,13,16,21 ,24-Hexaoxa-1 ,10-diazabicyclo[8.8.8]-hexacosane - Kryptofix®) or a crown ether (e.g.: 18—crown-6).

The 18F-Fluorination agent can also be a tetraalkylammonium salt of 18F' or a tetraalkylphosphonium salt of 18F', known to those skilled in the art, e.g.: tetrabutylammonium [18F]fluoride, tetrabutylphosphonium luoride.

Preferably, the 18F-Fluorination agent is Cs18F, K18F, tetrabutylammonium [18F]fluoride.

The ts, solvents and conditions which can be used for this fluorination are common and well-known to the skilled person in the field. See, e.g., J. Fluorine Chem, 27 (1985):177- 191; , Fluorine-18 Labeling Methods: Features and Possibilities of Basic ons, (2006), in: Schubiger P.A., Friebe M., Lehmann L., (eds), emistry - The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp.15-50). Preferably, the ts used in the present method are DMF, DMSO, acetonitrile, DMA, THF, or mixtures thereof, preferably the solvent is acetonitrile.

Heating can be done by conventional heating or micro wave heating.

In another preferred embodiment, the direct method for obtaining compounds of formula lVb- F18 ses the steps - Reacting compound of Formula lb with a 18F-Fluorination agent to obtain compound of formula lllb-F18, and - Deprotecting the obtained compound of formula 18 for obtaining compound of formula lVb-F18, wherein compound of formula lllb-F18 is o 0 H30 CH3 H3C o O+CH3 H3C HN_ CH3 18': Formula 18 R1 is triphenylmethyl (Trityl) and nd of formula lVb-F18 is O O HO OH 18': Formula lVb-F18 Optionally the method is followed by the purification of compound of Formula lVb-F18 by solid-phase-extraction. Preferably phase-extraction cartridges or columns are used.

The 18F-Fluorination agent can also be a tetraalkylammonium salt of 18F' or a tetraalkylphosphonium salt of 18F', known to those skilled in the art, e.g.: tetrabutylammonium [18F]fluoride, tetrabutylphosphonium [18F]fluoride.

The reagents, solvents and conditions which can be used for this fluorination are common and well-known to the d person in the field. See, e.g., J. Fluorine Chem, 27 (1985):177- 191; Coenen, Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions, (2006), in: Schubiger P.A., Friebe M., Lehmann L., (eds), emistry - The Driving Force in lar Imaging. Springer, Berlin Heidelberg, pp.15-50). Preferably, the ts used in the present method are DMF, DMSO, acetonitrile, DMA, THF, or mixtures thereof, ably the solvent is acetonitrile.

Heating can be done by conventional heating or micro wave heating.

In a red embodiment, a compound of formula IV is manufactured by reacting a 24 (followed by 24A) In an embodiment, the invention is directed to a nd prepared by any of the above described methods. 24A wed by 25) single isomers, tautomers, diastereomers, enantiomers, stereoisomers, stereoisomeric es or mixtures thereof and suitable salts thereof.

Preferably, compounds of a II relates to compounds with (28,4S)-configuration (compound of formula Ila) a Ila O 0 H30 CH3 H3c+o - O+CH3 H3C f HN CH3 wherein R1 is triphenylmethyl (Trityl) corresponding to di-tert-butyl (4S)(3-hydroxypropyl)— N-trityl-L-glutamate.

In another red embodiment, compounds of formula II relates to compounds with )—configuration (compound of formula llb) Formula llb O 0 H30 CH3 H3c+o O+CH3 H C HN CH 3 3 wherein R1 is nylmethyl (Trityl) corresponding to di-terf—butyl (4R)—4-(3-hydroxypropyl)- N-trityl-L-glutamate.

In another preferred embodiment, compounds of formula II relates to compounds with (28)- configuration (compound of formula llalb) Formula Ila/b O 0 H30 CH3 H3c+o O+CH3 H3C HN CH3 wherein R1 is triphenylmethyl (Trityl) corresponding to di-terf—butyl 4-(3-hydroxypropyl)—N- trityl-L-glutamate.

In a sixth aspect, the invention is ed to protected compounds of formula Ill-F 2012/057884 a lll-F O O H3C CH3 H3c+o O+CH3 H3C HN CH3 wherein R1 is triphenylmethyl (Trityl), F means fluorine atom and single isomers, tautomers, diastereomers, enantiomers, stereoisomers, stereoisomeric mixtures or mixtures thereof and suitable salts thereof.

Preferably, F is 18F or 19F.

More preferably, F is 18F (compound of formula Ill-F18).

Preferably, compounds of a III relates to compounds with (28,4S)-configuration (compound of formula Illa-F) Formula llla-F O 0 wherein R1 is triphenylmethyl (Trityl), and F means fluorine atom.

Preferably, F is 18F in compound of formula Illa-F.

A red compound of Formula Illa-F18 is t-butyl (4S)—4-(3-[18F]FIuoropropyI)—N-trity|— L-glutamate.

In another preferred, compounds of formula III s to compounds with (28,4R)— configuration (compound of formula lllb-F) Formula lllb-F o o H3C CH3 H3C o O+CH3 H3C HN CH3 wherein R1 is triphenylmethyl (Trityl), and F means fluorine atom.

Preferably, F is 18F in compound of formula lllb-F.

A preferred compound of Formula lllb-F18 is di-tert-butyl (4R)—4-(3-[18F]FIuoropropyl)—N-trityl- L-glutamate.

In a seventh aspect, the invention is directed to a ition comprising nd of formula I, la, ll, Ila, Ill-F, Illa-F, Illa-F18, lVa-F or lVa-F18 as defined in above aspects and included embodiments. Preferably, the composition ses compound of a I, la, lb, ll, Ila, llb, Ill-F, Illa-F, lllb-F, Illa-F18, lllb-F18, lVa-F18 or lVb-F18 as defined in above aspects and included embodiments. More preferably, the composition comprises compound of formula I, la, lb, ll, Ila, llb, Ill-F, Illa-F, lllb-F, Illa-F18, lllb-F18, as d in above aspects and included embodiments.

In a first embodiment, the invention is directed to a composition comprising compound of formula I or la or llb and suitable reactants for a quoro-IabeIing reaction and/or nts, inter alia, carriers, solvents or stabilizers.

The person skilled in the art is familiar with adjuvants which are le for the desired pharmaceutical ations, preparations or compositions on account of his/her expert dge.

Preferably, the composition comprises exemplified compounds, stereoisomers and mixtures thereof, and suitable salts thereof, and acceptable carriers or ts as described above.

In a second embodiment, the invention is directed to a composition comprising compound of formula II or Ila or llb as described above and optionally suitable adjuvants. These nts include, inter alia, carriers, solvents, or stabilizers.

The person skilled in the art is familiar with adjuvants which are suitable for the desired pharmaceutical formulations, preparations or compositions on account of his/her expert knowledge.

In a third embodiment, the ion is directed to a composition comprising compound of formula lV-F18 or 8 or lVb-F18, and pharmaceuticaIIy suitable nts. The administration of the compounds, pharmaceutical compositions or combinations according to 2012/057884 the invention is performed in any of the generally accepted modes of administration available in the art. Intravenous deliveries are preferred.

In an eighth aspect, the invention is directed to a kit sing one vial or more than one vial comprising a predetermined quantity of compounds of Formula I, preferably compounds of Formula la or lb. More preferably, the kit comprises compounds of Formula la.

Optionally the kit comprises an able carrier, diluent, ent or adjuvant.

Preferably, the kit comprises predefined quantity of compound of a I and one or more solid-phase extraction cartridges/columns for the cation of compound of Formula IV- F18.

Preferably, the Kit comprises physiologically acceptable vehicle or carrier and optional adjuvants and preservatives, reagents suitable to m the herein sed reactions and/or to generate the 18F labeling reagents. Furthermore, the kit may n instructions for its use.

General synthesis of compounds of the invention Definitions The terms used in the present invention are defined below but are not limiting the invention scope.

As used herein, the term rsor” refers to a compound, which can be used as a starting material for a radiolabeling reaction, where an riate leaving group of the precursor is replaced by the radioisotope [18F].

As used herein, the term “amine protecting group” refers to a chemical entity (such as, for example triphenylmethyl) chemically bound to an amine group, which inhibits participation of this amine group in chemical reactions (see Greene's Protective Groups in Organic Synthesis, P. Wuts, T. Greene (Wiley)).

As used herein, the term “hydroxyl protecting group” refers to a chemical entity (such as, for example terf-butyl) chemically bound to a hydroxyl group, which inhibits participation of this hydroxyl group in chemical reactions (see Greene's Protective Groups in Organic Synthesis, P. Wuts, T. Greene (Wiley)).

WO 50204 As used herein, the term “alkyl” refers to a 01-05 straight chain or branched chain alkyl group such as, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert—butyl, pentyl, isopentyl, tyl. Preferably, alkyl is C1-C3 straight chain or branched chain alkyl.

“Aryl” represents a mono- or bicyclic aromatic, carbocyclic bivalent radical having, as a rule, 6 to 10 carbon atoms, optionally substituted by one to four “Substituents”; by way of example and by preference phenyl or naphthyl.

“Biaryl” represents an aromatic l substituted by an identical aromatic radical.

Preferably, Biaryl is biphenyl. oaryl” represents an aromatic, mono- or bicyclic bivalent radical having, as a rule, 5 to , preferably 5 to 6, ring atoms and up to 3, preferably 1, hetero atoms from the series consisting of S, O and N; by way of e and including but not limited to l, furyl, pyrrolyl, thiazolyl, yl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, uranyl, benzothiophenyl, quinolinyl, isoquinolinyl, triazolyl, n said “Heteroaryl” is optionally substituted by one to four “Substituents”. Preferably, “Heteroaryl” is pyridyl or quinolinyl.

As used herein, the term “Arylsulfonyl” refers to aryl groups respectively linked to the respective scaffold by a yl group, i.e. -S(=O)2-O, with the aryl moiety being as defined above, such as for e p-toluenesulfonyl.

The term “halo” refers to fluoro, chloro, bromo, and iodo.

Whenever the term “substituted” is used, it is meant to indicate that one or more hydrogens at the atom indicated in the expression using "substituted" is / are replaced by one ore multiple moieties from the group comprising halogen, hydroxyl, nitro, C1-Cs-alkylcarbonyl, cyano, trifluoromethyl, C1-Cs-alkylsulfonyl, C1-Cs-alkyl, C1-Cs-alkoxy and C1-Ce-alkylsulfanyl, provided that the regular valency of the respective atom is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a pharmaceutical composition.

As used , Cn-Cm indicates the range of number of carbon atoms the respective moiety may feature, rated by but not limited to e.g. C1-Cs-alkyl or 01-06 alkoxy, which may feature 1, 2, 3, 4, 5, or 6 carbon atoms not covering optional additional tution. lf chiral centres or other forms of isomeric centres are not otherwise defined in a compound according to the present invention, all forms of such stereoisomers, including enantiomers and diastereoisomers, are intended to be covered herein. Compounds containing chiral centres may be used as racemic mixture or as an enantiomerically enriched 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. In cases wherein compounds may exist in tautomeric forms, each tautomeric form is contemplated as being included within this ion r existing in equilibrium or predominantly in one form.

As used herein, the term “solvents” refers to inorganic such as water, as well as organic compounds such as acetonitrile and their mixtures used for dissolution of other solid, liquid or gaseous compound(s).

As used herein, the term “kit” refers to a set of the materials (such as filters) and chemicals (such as a precursor or solvents) required for the performing of the single radiolabeling process Radiolabeling As used herein, the term “radiolabeling” refers to a chemical process, where a ctive e (such as 18F) is attached to a selected molecule (such as a precursor).

Deprotection As used , the term “deprotection” refers to one or more chemical reaction(s), where a protecting chemical group such as trityl is eliminated from the molecule and the functional group of the molecule such as amino-group is ablished Desilylation As used herein, the term “ desilylation” refers to one or more chemical reaction(s), where a silyl group R3 — Si such as tert—butyldimethylsilyl is eliminated from the le and replaced by a proton.

WO 50204 Crystallization As used herein, the term “crystallization” refers to a physico-chemical process, where a solid crystals are precipitating from a solution, melt or gas.

As used herein, the term “bearing” means or is equivalent to substituted.

Experimental Section Abbreviations 4, 7, 13, 16, 21, 24-hexaoxa-1,10- diazabicyclo[8.8.8]-hexacosane (Kryptofix 222) Correspond to the observed reaction rate based on the amount of t measured in the reaction mixture at ent time points.

Correspond to the relative reaction rate, precursor used as reference and defined with the value “1”. 'b . .0-9 nuclear magnetic nce spectroscopy : chemical shifts (6) are given in ppm.

;U_| General: All solvents and chemicals were obtained from commercial sources and used t further purification. Anhydrous solvents and inert atmosphere (nitrogen or argon) were used if not stated otherwise. The preceding table lists the abbreviations used in this paragraph and in the Intermediates and Examples sections as far as they are not explained within the text body. NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.

Reactions were monitored by methods known to the person skilled in the art, such as thin- layer chromatography on suitable stationary phases, such as silica gel coated plates of aluminium or glass, or HPLC/UV analyses.

The compounds and intermediates ed 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 n cases, the nds may be purified by crystallization. In some cases, impurities may be removed by trituration using a suitable solvent. In some cases, the compounds may be purified by column chromatography, Column chromatography, as used hereinafter, typically refers to ative liquid chromatography on a suitable stationary phase, such as commercial silica gel or prepacked silica gel cartridges, e.g. Merck silica gel 60 (230-400 mesh) and eluents such as gradients of ethyl acetate/n-hexane.

Radiolabeling: All als were purchased from commercial sources, h and Merck, and used t further purification.

Radiochemical synthesis were med using a GE MX tracerlab module. Analytical HPLC was performed on an Agilent 1200 system. HPLC solvents were purchased from h.

GENERAL SES A. Alkylation of glutamate backbone Compounds of the invention can be approached by alkylation of glutamate derivatives A- 1 as shown in Scheme 2.

H:C:+OW4Y3,= HN\RA3 RAZ J/ H3C 0 0 HN A3 CH3 R H30 CH3 H3c+o O+CH3 A-1 A-2 H30 HNxRA3 CH3 FEM A-4 Scheme 2 Alkylation of glutamate backbone (RA1 is a hydroxyl protecting group, RA2 is a leaving group, RA3 is an amine protecting group) RA2 acts as a leaving group (for example Br, I, sulfonate) and RA1 is a protecting group.

The alkylation of glutamate derivatives is bed in the literature, e.g.: M. A. Brimble et al., Bioorg. Med. Chem. 2005, 13, 519-523; S. Hanessian et al., J. Org. Chem. 2005, 70, 5070-5085; S. Hanessian et al., Org. Lett. 2004, 6, 4683-4686; J. Zhang et al., Tetrahedron Lett. 2003, 44, 1413-1415. It is well know, that the alkylation affords selectively compounds A-3 if R1 is a carbamate-type protecting group (e.g. Boc, CBz).

Mixtures of A-3 and A-4 can be obtained and separated by chromatography methods if other protecting groups are used (e.g. R’"3 = ).

Methods are well known to the person skilled in the art to t compounds of formulae A- 3 to compounds of formula Ila, including e.g.: : - Cleavage of amine protecting group RA3and introduction of amine ting group R1 (e.g. introduction of Trityl group via triphenylmethyl chloride) - Cleavage of hydroxyl protecting group RA1 (e.g. desilylation desilylation using TBAF) r methods for the synthesis of Ila are well known to the person skilled in the art, e.g.

Allylation of A-1 using allyl bromide and subsequent hydroboration.

B. Synthesis of sulfonates Precursors for 18F-alkyl compounds of general Formula I and la can be synthesized from the respective hydroxyl compounds of general a II and Ila ing to methods known in the art (J. March, Advanced Organic Chemistry, 4th ed. 1992, John Wiley & Sons, pp 352ff).

C. 18F Fluorination The radiosynthesis of the 18F labeled compounds of the invention can be accomplished in multiple ways using known methods described in the ture and databases in reach of the person d in the art.

More specifically, compounds according to the general Formulae Ill-F18 and lV-F18 can be synthesized starting from I as outlined in Scheme 4. Such nucleophilic fluorinations are known to the person skilled in the art and also described in the literature, for s and cited references within see e.g. Cai et al., Eur. J. Org. Chem., 2008, 2853; Ametamey eta/., Chem. Rev., 2008, 108, 1501, Miller et al., Angew. Chem. Int. Ed. 2008, 47, 8998. o o H30 CH3 o 0 0 o H c+o 0+ H c CH CH3 3 3 :1 c HN CH3 H3c+o O+CH3 HO OH ‘R1 —> H3C HN‘ CH3 R1 _> NH2 0 o :s', I 18F "Hm 18F lV-F18 A 0 Scheme 4 Synthesis of 18F-labeled compounds of Formula Ill-F18 and lV-F18 WO 50204 HPLC methods Method A1 (analytics of di-tert-butyl (4S)(3-hydroxypropyl)-N-trityl-L-glutamate Column: ChiralPak IA, 4.6x250 mm Mobile phase: 5% IPA/n-heptane Flow rate: 1 mL/min Wavelength: 214/254 nm Method A2 (for Id) Column: ge Mobile phase: Acetonitrile/water 20:80 to 100% water Flow rate: 1 mL/min Wavelength: 214 nm Method A3 (for la to lc and le to Ii) Column: X-Bridge Mobile phase: Acetonitrile/water 15:80 to 100% water Flow rate: 1 mL/min Wavelength: 214 nm Method A4 luorination) Column: Phenomenex Lux 5U Amylose-2 Mobile phase: 10% IPA/Hex Flow rate: 1 mL/min Wavelength: 214 nm Method A5 (18F-radiolabeling) : Phenomenex Luna 5p C18(2); 250*4.6mm Mobile phase: A: Na2HPO4 10 mM pH 7.4, B: acetonitrile Gradient: 0 min 12% B, 15 min 12% B, 16 min 100% B, 18 min 100% B, 20 min 12% B, 23 min 12% B Flow rate: 1.2 mL/min Wavelength: 340 nm Derivatization: 10 ml of the product solution are mixed with 30 ml OPA reagent (Thermo Scientific, No.:26015). After 1 min reaction at room temperature the solution is applied to the HPLC Preparation of Intermediates | O O O O TfOWOTBDMS H3C CH3 H3C CH3 ch+o O+CH3 —> ch+o O+CH3 —> H3C | CH3 “30 HN. CH3 O O O 0 H3C+OWLOHBO CH3 H2/Pd H C CH Trt-Cl {CH3 _> H3C+OWO+CH3 —>3 3 H30 f HN‘ CH3 H3C = f NH 2 CH3 TBDMSO TBDMSO O O O 0 H30 CH3 TBAF H3C CH3 ch+o O+CH3 —> ch+0 5 O+CH3 H c CH H C = HN\Trt 3 3 J/ HN 3 J/ \Trt 3 TBDMSO HO 1. Cbz protection To a on of di-tert-butyl L-glutamate hloride (3.0 g, 10.14 mmol) and DIPEA (5.3 mL, 30.4 mmol) in dichloromethane (60 mL) was added a solution of benzyl chloroformate (1.74 mL, 12.2 mmol) in dichloromethane (30 mL). The solution was stirred for 30 min at room temperature. After evaporation of the solvents, the residue was taken up with ethyl acetate and water. The organic phase was separated, washed with water and brine, and was dried over sodium sulfate. After filtration, the solution was evaporated and the crude product was purified by flash chromatography (ethyl acetate/n-hexane: 10/90 to 20/80) to give the desired product (3.65 g, 91%) as a colorless oil. 1H NMR (400 MHz, CDCls) 8 ppm 1.43 (s, 9H), 1.46 (s, 9H), 1.84-1.96 (m, 1H), 2.06-2.18 (m, 1H), 2.20-2.40 (m, 2H), 4.20-4.30 (q, J = 8.0 Hz, 1H), 5.10 (s, 2H), 5.34 (d, J = 8.0 Hz, 1H), 7.27-7.40 (m, 5H). 2. Alkyation A solution of di-tert-butyl N-[(benzyloxy)carbonyl]—L-glutamate (4.77 g, 12.12 mmol) in THF (76 mL) was cooled to -78°C and a 1.0 M on of lithium bis(trimethy|si|y|)amide (25.45 mL, 25.45 mmol) in THF was added slowly. The solution was stirred for 45 min at -78°C, and a solution of 3-(tert-butyldimethylsilyloxy)propyl trifluoromethanesulfonate (5.08 g, 15.76 mmol) in THF (25 mL) was added drop wise at -78°C. After stirring for 2 h, the reaction mixture was quenched with 2.0 N aqueous solution of NH4CI, and warmed up to room temperature, and concentrated under vacuum. The resulting aqueous on was extracted with ethyl acetate, the ed organic phase was washed with water and brine, and dried over sodium sulfate. After filtration, the solution was evaporated and the crude product was purified by flash chromatography (ethyl acetate/n-hexane 10/90) to give the desired product (4.62 g, 67%) as a colorless oil. 1H NMR (400 MHz, CDCIs) 6 ppm 0.04 (s, 6H), 0.88 (s, 9H), 1.42 (s, 9H), 1.45 (s, 9H), 1.48- 1.62 (m, 4H), .86 (m, 1H), 1.90-2.00 (m, 1H), 2.30-2.40 (m, 1H), 3.50-3.62 (m, 2H), 4.16-4.25 (q, J = 8.8 Hz, 1H), 5.10 (s, 2H), 5.14 (d, J = 8.8 Hz, 1H), 7.28-7.38 (m, 5H); 13c NMR (100 MHz, CDCls) 6 -5.30, 18.31, 25.93, 27.95, 28.03, 29.12, 30.01, 34.32, 43.14, 53.75, 62.71, 66.89, 80.68, 82.12, 110.00, 128.09, 128.12,128.46, 136.27,156.02,171.53, 174.93; MS (ESI, ve ion mode) C30H51NO7Si: m/z 588.5 [(M+Na]+]. 3. Cbz deprotection and Trityl protection To a solution of di-tert-butyl (4S)-N-[(benzyloxy)carbonyl](3-{[tert-buty|(dimethyl) silyl]oxy} propy|)-L-g|utamate (4.158 g, 7.349 mmol) in MeOH (140 mL) was added 10% Pd/C (2.346 g, 2.2046 mmol) under argon atmosphere. After flushing with hydrogen gas, the solution was suspended for 18 h at room temperature. After filtration with celite, the solution was evaporated. The residue was dissolved in dichloromethane (130 mL). DIPEA (3.5 mL, 20.337 mmol) and triphenylmethyl chloride (2.268 g, 8.135 mmol) were added. The reaction mixture was stirred for 2 h at room ature, and then water was added. The reaction mixture was extracted with dichloromethane. The ed organic solution was washed with water, and dried over sodium sulfate. After filtration, the solution was ated and the crude product was ed by flash chromatography (ethylacetate/n-hexane: 5/95) to give the desired product (3.64 g, 79% l yield) as a colorless oil. 1H NMR (400 MHz, CDCIs) 8 0.05 (s, 6H), 0.90 (s, 9H), 1.16 (s, 9H), 1.33 (s, 9H), 1.46-1.72 (m, 5H), 2.12-2.22 (m, 1H), 2.28-2.40 (m, 1H), 2.70-2.82 (m, 1H), 3.20-3.30 (m, 1H), 3.59 (t, J = 5.6 Hz, 2H), 7.15-7.20 (m, 3H), 7.20-7.28 (m, 6H), 7.42-7.52 (m, 6H); 13C NMR (100 MHz, CDCIs) 8 -5.26, 18.35, 25.98, 27.87, 28.06, 29.93, 30.41, 39.04, 42.67, 55.27, 62.84, 71.14, 80.04, 80.84, 126.31, 127.79, 128.89, 146.35, 174.58, 174.67; MS (ESI) C41H59N058i: m/z 696.9 [(M+Na)+] 4. Desilylation To a sol utio n of t-butyl (4S)—4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-N-trityl-L- glutamate (3.64 g, 5.40 mmol) in THF (40 mL) was added TBAF (1.0 M in THF, 10.8 mL, .8 mmol). The solution was stirred for 1.5 h at room temperature. After evaporation of the solvent, the crude product was purified by flash chromatography (ethyl acetate/n-hexane 40/60) to give the desired product (2.55 g, 84%) as a white solid. 1H NMR (400 MHz, CDCls) 8 ppm 1.15 (s, 9H), 1.32 (s, 9H), 1.50-1.76 (m, 5H), 2.10-220 (m, 1H), 2.30-2.40 (m, 1H), 2.70-2.82 (m, 1H), 3.20-3.30 (m, 1H), 3.61 (t, J = 5.6 Hz, 2H), 7.12- 7.18 (m, 3H), 7.20-7.28 (m, 6H), 7.42-7.50 (m, 6H); 13c NMR (100 MHz, coc13) 6 27.86, 28.04, 29.59, 30.26, 39.10, 42.63, 55.27, 62.49, 71.16, 80.33, 80.96, 126.34, 127.80, 128.87, 146.29, , 174.68; MS (ESI) C35H45N05: m/z 582.6 )+] Chiral HPLC analysis of di-tert-butyl (4S)(3-hydroxypropyl)-N-trityl-L-glutamate was done according the method A1 (retention time: 7-8 min).

General procedures 19F-Fluorination: Precursor (0.01 mmol) was dissolved in acetonitrile (0.5 mL), and 1.0 M TBAF/acetonitrile solution (20 uL, 0.02 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h. 40 pL of solution was taken at 5, 10, 20, 40, 60, 90, and 120 min for HPLC analysis (method A4). 18F-Fluorination: [18F]Fluoride (380-1400 MBq) was trapped on a QMA cartridge s, SepPak light). The activity was eluted with 0.6 mL kryptofix2.2.2/potassium carbonate solution (3 mg / 0.6 mg) in acetonitrile/water into the reaction vessel. The mixture was dried (95°C, nitrogen , vacuum). 6 mg of precursor in 1.5 mL acetonitrile were added to the dried residue and the resulting solution was d at 120°C ayed r temperature) for 5 min.

Subsequently, approx. 1.5 mL 2 M HCI was added. The mixture was heated at 120°C for 4.2 min.

The reaction mixture was diluted with 10 ml water and was transferred to 2 MCX cartridges (Waters, Oasis MCX plus extraction cartridge). The cartridges were washed with 10 ml of water and subsequently eluted with 15 ml phosphate buffer (containing 10.5 mg Na2HPO4 x 2H20, 9 mg NaCl). The t solution is transferred via a Hypercarb cartridge (Thermo Scientific, Hypersep Hypercarb 500 mg/ 6 ml) to the final product vial.

HPLC analytics of the resulting product is performed using method A5.

Identity of lV-F18 was confirmed by co-elution with nce compound lV-F19 and UV detection at 340 nm (retention time: 12-13 min).

Exam |e com ounds of theinvention Precursor com ounds l Formula | CH O O 3 ”30% J<CHS H30 0 0 CH3 HN O 9 o NO lc 'a 2 ﬂ N * O \ Id le C' 6 lg lh I] la t-butyl (4S)—4-(3-{[(4-nitrophenyl)su|fony|]oxy}propy|)-N-trity|-L-g|utamate CH O 0 CH3 HC 3 3>k J<CH3 H3C o - 0 CH3 J/ HN [O 9 00 To a solution of di-tert-butyl (4S)(3-hydroxypropyl)-N-trity|-L-g|utamate (212.6 mg, 0.38 mmol) and triethylamine (159 uL, 1.14 mmol) in dichloromethane (5 mL) was added 4- nitrobenzenesulfonyl de (126 mg, 0.57 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 h and then water was added. The organic layer was separated, and aqueous WO 50204 layer was extracted with dichloromethane. The combined c solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/n-hexane = 15/85) to give the desired product (231 mg, 82%) as a white solid. 1H NMR (400 MHz, CDCls) 8 ppm 1.14 (s, 9H), 1.30 (s, 9H), .73 (m, 5H), 2.00-2.12 (m, 1H), 2.22-2.32 (m, 1H), 2.75 (d, J: 9.2 Hz, 1H), 3.20-3.27 (m, 1H), 4.12 (t, J: 6.4 Hz, 2H), 7.14-7.19 (m, 3H), 7.20-7.27 (m, 6H), 7.42-7.47 (m, 6H), 8.09 (d, J = 8.8 Hz, 2H), 8.38 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCI3) 8 26.63, 27.83, 28.00, 29.03, 38.57, 42.20, 55.16, 71.18, 71.34, 80.64, 81.05, 124.48, 126.41, 127.83, 128.81, 129.20, , 146.17, 173.87, 174.33; MS (ESI, positive ion mode) C41H48N2098 : m/z 767.6 [M+Na]+. lb Di-tert-butyl (4S)—4-(3-{[(3-nitrophenyl)sulfonyl]oxy}propy|)-N-trity|-L-g|utamate CH o 0 CH3 H3CS\3 J(CH3 H30 0 - 0 CH3 To a solution of di-tert-butyl (4S)—4-(3-hydroxypropyl)-N-trity|-L-g|utamate (206.2 mg, 0.37 mmol) and triethylamine (154 uL, 1.10 mmol) in dichloromethane (5 mL) was added 3- enzenesulfonyl chloride (122 mg, 0.55 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 h and then water was added. The organic layer was ted, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl e/n-hexane = 20/80) to give the desired product (215 mg, 78%) as a white solid. 1H NMR (400 MHz, CDCls) 6 ppm 1.14 (s, 9H), 1.30 (s, 9H), 1.50-1.73 (m, 5H), 2.03-2.12 (m, 1H), 2.23-2.32 (m, 1H), 2.75 (d, J = 8.4 Hz, 1H), 3.20-3.27 (m, 1H), 4.13 (t, J = 6.4 Hz, 2H), 7.14-7.19 (m, 3H), 7.20-7.27 (m, 6H), 7.42-7.47 (m, 6H), 7.77 (t, J = 8.2 Hz, 1H), 8.22 (dq, J = 0.8, 8.0 Hz, 1H), 8.50 (dq, J = 0.8, 8.0 Hz, 1H), 8.75 (t, J = 1.8 Hz, 1H); 13C NMR (100 MHz, CDCls) 6 26.63, 27.82, 27.97, 29.03, 38.65, 42.24, 55.12, 71.14, 71.32, 80.62, 81.03, 123.13,126.38,127.80,128.18,128.81,130.74,133.24,138.31,146.17,173.84,174.34; MS (ESI, positive ion mode) C41H48N2098 : m/z 767.8 [M+Na]+. lc Di-tert-butyl (4S){3-[(biphenylylsulfonyl)oxy]propy|}-N-trityl-L-glutamate To a solution of di-tert-butyl (4S)—4-(3-hydroxypropyl)-N-trityl-L-glutamate (202.8 mg, 0.36 mmol) and triethylamine (151 uL, 1.09 mmol) in dichloromethane (5 mL) was added biphenylsulfonyl chloride (137 mg, 0.54 mmol) at 0°C. The reaction mixture was stirred at 0°C for 5 h and then water was added. The organic layer was separated, and aqueous layer was extracted with dichloromethane. Combined c solution was dried over sodium sulfate, and concentrated in vacuo. The e was purified by flash column tography (ethyl acetate/n-hexane = 10/90) to give the desired product (236 mg, 84%) as a white solid. 1H NMR (400 MHz, CDCls) 8 ppm 1.14 (s, 9H), 1.30 (s, 9H), 1.50-1.73 (m, 5H), 2.03-2.12 (m, 1H), 2.23-2.32 (m, 1H), 2.70-2.80 (m, 1H), 3.18-3.27 (m, 1H), 4.06 (t, J = 6.4 Hz, 2H), 7.12- 7.17 (m, 3H), 7.20-7.27 (m, 6H), 7.40-7.52 (m, 9H), 7.58-7.62 (m, 2H), .76 (m, 2H), 7.94-7.98 (m, 2H); 13C NMR (100 MHz, CDCls) 8 26.66, 27.85, 28.00, 29.26, 38.74, 42.35, 55.14, 70.38, 71.16, 80.51, 80.99, 126.37, 127.38, 127.81, , 128.39, 128.70, 128.84, 129.10,134.50, 139.04, 146.21,146.72,173.98, 174.41; MS (ESI, positive ion mode) C47H53N078 : m/z 798.5 [M+Na]+.

Id Di-tert-butyl (4S)—4-{3-[(2-naphthylsulfonyl)oxy]propy|}-N-trityl-L-glutamate H30 0 o CH3 f: HN O To a solution of di-tert-butyl (4S)—4-(3-hydroxypropyl)-N-trityl-L-glutamate (217.5 mg, 0.39 mmol) and triethylamine (160 uL, 1.17 mmol) in dichloromethane (5.0 mL) was added alenesulfonyl chloride (155.4 mg, 0.58 mmol) at 0°C. The reaction mixture was stirred at 0°C for 3 h and then water was added. The organic layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was ed by flash column chromatography (ethyl acetate/n-hexane = 12/88) to give the desired product (289 mg, 82%) as a white solid (mp. = 119.3°C). 1H NMR (400 MHz, CDCls) 8 1.12 (s, 9H), 1.27 (s, 9H), 1.50-1.70 (m, 5H), 2.00-2.10 (m, 1H), 2.22-2.32 (m, 1H), 2.74 (d, J = 8.8 Hz, 1H), 3.14-3.24 (m, 1H), 4.04 (t, J = 6.4 Hz, 2H), 7.10- 7.16 (m, 3H), 7.18-7.24 (m, 6H), .46 (m, 6H), .72 (m, 2H), 7.85 (dd, J = 1.6, 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.96-8.02 (m, 2H), 8.48 (d, J = 1.2 Hz, 1H);13C NMR (100 MHz, CDCls) 8 26.6, 27.8, 27.9, 29.2, 38.7, 42.3, 55.1, 70.4, 71.1, 80.5, 80.9, 122.5, 126.3, 127.8,128.0,128.8,129.3,129.7,131.9,132.8,135.2,146.2,173.9,174.4;MS(ES|, positive ion mode) C45H51N078: m/z 772.9 [M+Na]+. le Di-tert-butyl (4S)—4-{3-[(1-naphthylsulfonyl)oxy]propy|}-N-trityl-L-glutamate CH o 0 CH H3C o : 0 CH3 To a solution of di-tert-butyl (4S)(3-hydroxypropyl)-N-trityl-L-glutamate (216.8 mg, 0.39 mmol) and triethylamine (160 uL, 1.16 mmol) in dichloromethane (5.0 mL) was added naphthalenesulfonyl chloride (131.7 mg, 0.58 mmol) at 0°C. The reaction mixture was d at 0°C for 3 h and then water was added. The c layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/n-hexane = 12/88) to give the desired product (248 mg, 85%) as a white solid. 1H NMR (400 MHz, CDCls) 6 1.12 (s, 9H), 1.25 (s, 9H), 1.48-1.64 (m, 5H), 1.96-2.18 (m, 1H), 2.16-2.26 (m, 1H), 2.73 (d, J = 9.2 Hz, 1H), 3.10-3.20 (m, 1H), 3.90-4.00 (m, 2H), 7.10-7.16 (m, 3H), 7.18-7.24 (m, 6H), .46 (m, 6H), 7.56 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCls) 6 26.5, 27.8, 27.9, 29.2, 38.7, 42.3, 55.0, 70.5, 71.1, 80.4, 80.9, 124.0, 124.9, 126.3, 127.2, 127.8, 128.4, 128.7, 128.80, 128.83, 130.4, 131.2, 134.1, 135.2, 146.2,173.9, 174.4; MS (ESI, positive ion mode) C45H51NO7S: m/z 772.8 +.

If Di-tert-butyl (4S)—4-{3-[(quinolinylsulfonyl)oxy]propyl}-N-trityl-L-glutamate H3Cj\H3 O O J<3CH3 H30 0 0 CH3 f: HN O To a solution of di-tert-butyl (4S)—4-(3-hydroxypropyl)-N-trityl-L-glutamate (203.4 mg, 0.36 mmol) and triethylamine (150 uL, 1.09 mmol) in dichloromethane (5.0 mL) was added quinolinesulfonyl chloride (124.1 mg, 0.55 mmol) at 0°C. The reaction mixture was stirred at 0°C for 3 h and at room temperature for ght and then water was added. The organic layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium e, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/CH2CI2 = 1/99) to give the desired product (140 mg, 51%) as a white solid. 1H NMR (400 MHz,CDCI3)81.11 (s, 9H), 1.26 (s, 9H), 1.46-1.74 (m, 5H), 2.00-2.30 (m, 1H), .28 (m, 1H), 2.72 (d, J = 9.2 Hz, 1H), 3.12-3.22 (m, 1H), 4.31 (t, J = 6.4 Hz, 2H), 7.12- 7.16 (m, 3H), 7.20-7.26 (m, 6H), 7.40-7.46 (m, 6H), 7.56 (dd, J = 8.4, 4.2 Hz, 1H), 7.53-7.68 (m, 1H), 8.12 (dd, J = 8.2, 1.6 Hz, 1H), 8.26 (dd, J = 2.0, 8.2 Hz, 1H), 8.50 (dd, J = 72,16 2012/057884 Hz, 1H), 9.16 (dd, J = 1.6, 4.2 Hz, 1H); 130 NMR (100 MHZ, CDCls) 8 26.9, 27.8, 27.9, 29.4, 38.8, 42.4, 55.1, 71.1, 71.5, 80.4, 80.9, 122.4, 125.2, 128.3, 127.8, 128.8, 129.0, 133.1, 134.8, 138.4, 148.2, 151.9, 173.9, 174.4; MS (ESI, positive ion mode) C44H50N2078: m/z 773.9 [M+Na]+. lg Tetra-tert-butyl ,2'S,4'S)—2,2'-[biphenyl-4,4'-diylbis(sulfonyloxypropane-3,1- diyl)]bis[4-(tritylamino)pentanedioate] To a solution of di-tert-butyl (4S)—4-(3-hydroxypropyl)-N-trityl-L-glutamate (209.6 mg, 0.37 mmol, 2.2 eq) and triethylamine (140 uL, 1.02 mmol) in dichloromethane (5.0 mL) was added biphenyl4’-disulfonyl chloride (60 mg, 0.17 mmol) at 0°C. The reaction mixture was stirred at 0°C for 3 h and at room temperature for overnight and then water was added. The c layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and trated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/n-hexane = 25/75) to give the desired product (98.7 mg, 41%) as a white solid. 1H NMR (400 MHz, CDCls) 8 1.16 (s, 9H), 1.30 (s, 9H), 1.50-1.76 (m, 5H), 2.04-2.14 (m, 1H), 2.24-2.34 (m, 1H), 2.75 (d, J = 9.2 Hz, 1H), 3.18-3.28 (m, 1H), 4.08 (t, J = 6.4 Hz, 2H), 7.12- 7.18 (m, 3H), 7.20-7.26 (m, 6H), 7.40-7.46 (m, 6H), 7.72 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCls) 8 26.6, 27.8, 28.0, 29.2, 38.6, 42.3, 55.1, 70.6, 71.2, 80.5, 81.0, 126.4, 127.8, 128.2, 128.6, 128.8, 136.1, 144.4, 146.2, 174.0, 174.4; MS (ESI, positive ion mode) N201482: m/z 1420.6 [M+Na]+. lh Di-tert-butyl (4S)—4-[3-({[4-nitro(trifluoromethyl)phenyl]sulfony|}oxy)propy|]-N-trity|-L- glutamate To a solution of di-tert-butyl (4S)—4-(3-hydroxypropyl)-N-trity|-L-g|utamate (439 mg, 0.78 mmol) and triethylamine (330 uL, 2.35 mmol) in dichloromethane (7.0 mL) was added 4-nitro- 3-(trifluoromethyl)benzenesulfonyl chloride (340.7 mg, 1.18 mmol) at 0°C. The reaction mixture was stirred at 0°C for 45 min and then water was added. Organic layer was ted, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was ed by flash column chromatography (ethyl acetate/n-hexane = 15/85) to give the desired product (4h, 470 mg, 74%) as a light yellow solid. 1H NMR (400 MHz, CDCls) 8 1.14 (s, 9H), 1.30 (s, 9H), 1.52-1.80 (m, 5H), 2.04-2.14 (m, 1H), 2.24-2.34 (m, 1H), 2.76 (d, J = 8.8 Hz, 1H), 3.20-3.28 (m, 1H), 4.17 (t, J = 6.0 Hz, 2H), 7.16- 7.20 (m, 3H), 7.20-7.28 (m, 6H), 7.42-7.48 (m, 6H), 7.97(d, J = 8.4 Hz, 1H), 8.23 (dd, J = 2.0, 8.4 Hz, 1H), 8.34 (d, J = 1.6 Hz, 1H); MS (ESI, ve ion mode) C42H47F3N2098: m/z 835.4 [M+Na]+.

Ii Di-tert-butyl (4S)—4-(3-{[(2,4,6-trichlorophenyl)sulfonyl]oxy}propy|)-N-trity|-L-g|utamate CH3 0 0 CH3 H \OWOJ<CH:CH J/ HN [0 To a solution of t-butyl (4S)—4-(3-hydroxypropyl)-N-trityl-L-glutamate (438 mg, 0.78 mmol) and triethylamine (327 uL, 2.35 mmol) in romethane (7.0 mL) was added 2,4,6- trichlorobenzenesulfonyl chloride (328.6 mg, 1.17 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h and then water was added. The organic layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and trated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/n-hexane = 10/90) to give the desired product (415 mg, 66%) as a white solid. 1H NMR (400 MHz,CDCI3)81.15(s,9H), 1.31 (s, 9H), 1.52-1.80 (m, 5H), 2.04-2.16 (m, 1H), 2.26-2.36 (m, 1H), 2.77 (d, J = 9.6 Hz, 1H), 3.18-3.24 (m, 1H), 4.15 (t, J = 6.4 Hz, 2H), 7.12- 7.18 (m, 3H), 7.20-7.28 (m, 6H), 7.42-7.48 (m, 6H), 7.50 (s, 2H); 13C NMR (100 MHz, CDCls) 8 26.5, 27.8, 28.0, 29.2, 38.7, 42.2, 55.1, 71.1, 71.4, 80.5, 81.0, 126.3, 127.8,128.8,130.9, 131.2, 136.7, 139.3, 146.1, 173.8, 174.3; MS (ESI, positive ion mode) C41H45CI3N078: m/z 826.3 [M+Na]+. lj Di-tert-butyl (4S)—4-(3-{[(7-nitronaphthyl)sulfonyl]oxy}propyl)-N-trityl-L-glutamate CH o 0 CH w w H3C o 0 CH3 J/ HN [0 CR oO To a solution of di-tert-butyl (4S)—4-(3-hydroxypropyl)-N-trityl-L-glutamate (486 mg, 0.84 mmol) and triethylamine (350 uL, 2.58 mmol) in dichloromethane (7.0 mL) was added 5-nitronaphthalenesulfonyl de (340.8 mg, 1.25 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 h and water was added. The organic layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was ed by flash column chromatography (ethyl acetate/n-hexane = 20/80) to give the desired t (616 mg, 93%) as a white solid. 1H NMR (400 MHz, CDCls) 6 1.12 (s, 9H), 1.28 (s, 9H), .74 (m, 5H), 2.00-2.12 (m, 1H), 2.20-2.30 (m, 1H), 2.74 (d, J = 8.0 Hz, 1H), 3.12-3.24 (m, 1H), 4.11 (t, J = 6.4 Hz, 2H), 7.10- 7.18 (m, 3H), .26 (m, 6H), 7.38-7.46 (m, 6H), 7.73 (t, J = 7.6 Hz, 1H), 8.04-8.10 (m, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 7.6 Hz, 1H), 8.58 (s, 1H), 8.77 (d, J = 9.2 Hz, 1H); 13C NMR (100 MHz, CDCls) 6 26.6, 27.8, 28.0, 29.1, 38.6, 42.2, 55.1, 70.9, 71.1, 80.5, 81.0, 125.4, 125.9, 126.3, 127.01, 127.04, 127.8, 128.8, 129.8, 133.0, 134.8, 135.8, 146.2, 146.4, 173.9, 174.3; MS (ESI, positive ion mode) C45H50N2098: m/z 817.5 [M+Na]+. lization Crystallization was done for compound Id. 2% ether/hexane was used for this crystallization.

Crystallization was obtained for compound Id. 19F-fluorination of example compounds 19F-Fluorination was performed as bed in “General procedures”. The progress of the reaction was examined after 5, 10, 20, 40, 60, 90, and 120 min. Plotting the percentage of the conversation versus the time, the reaction rates were calculated. For calculation of the relative reaction rates, the t reaction (19F-fluorination of If) was defined as 1. Fastest conversion was found for the compounds la, lb and especially for lg. The compounds lc, Id, le; Ii and I] exhibited r reaction rates compared to If.

Table 1 Reaction rates of precursors 0.466 0.663 0.196 0.159 0.165 0.067 0.796 0.126 0.0894 6.93 9.86 2.93 2.38 2.45 n 11.8 1.88 1.33 Data correspond to the reaction rates measured for 19F-fluorination of the precursors. 18F-fluorination of exam le com oundsl 18F-Fluorination was performed as described in “General procedures”. Radiochemical yields and purities as shown in table 2 were determined.

WO 50204 The radiochemical yield was calculated by the ratio of product radioactivity and ng radioactivity. Both are measured using a dose calibrator (MED Nuklearmedizin Technik Dresden). The radiochemical purity is determined by analytical HPLC (method A5).

Table 2 Radiolabeling of precursors “—-Epimeric Radiochemical yield Precursor Ratio (4S:4R) % (d.c) -——56 ———38 -_——45 u——51 u——39 Table 2 indicates that for all compounds high radiochemical yields (38-56% n.d.c.) have been obtained.

Furthermore, table 2 shows that the radiolabeling ed in high stereochemical es for the compounds la — I] (93/7 — 99/1).

Stability of example compounds The stability of the compounds of formula I were examined in solid form at two different temperatures: 0°C, and -20°C. The precursors were tested weekly for 4 weeks. Before the study, purities of the precursors were determined individually by HPLC analysis.

Compound sampling 1. Solid state: 3-5 mg of the respective sor la to I] were put into 8 amber vials, which were flushed with Ar gas and capped. Each four vials containing precursor were stored at 0°C, and -20°C. Every week for 4 weeks, 1 mg of precursor was dissolved in acetonitrile (1.0 mL). 10 uL of solution was ed into HPLC (method A2 or A3, respectively).

Table 3 Summary of stability study Solid (%) "I.“94.6 94.8 95.0 93.7 91.3 94.3 98.6 98.6 98.7 98.6 m 98.4 98.0 "I.99.8 99.8 99.8 99.8 99.8 "I“ 98.9 WWW98.6 98.6 97.9 89.6 89.0 88.5 89.0 88.3 89.0 87.0 0 98.0 98.1 97.9 97.9 97.8 97.5 "I.94.6 95.0 94.8 93.1 93.1 93.4 92.8 “I.89.6 97.0 97.0 96.7 95.6 95.9 93.2 "I.97.2 97.1 97.0 96.8 m 96.3 m ND: not determined Pre aration of Intermediates || o o o 0 ch+oWoH30 CH3 H3c CH3 CH3 —> ch+o O+CH3 —> H30 NH2*HC| CH3 H30 HN\Trt CH3 0 O O O HsC CH3 H3C CH3 H30+O O+CH3 —> ch+o O+CH3 H30 HN CH3 H30 HN CH3 Trt Trt

Claims

. Trityl grotection Tritylchloride (2.05 g. 7.36 mmol) was added to a solution of di-tert—butyl amate hloride (2.15 g, 7.27 mmol) and ylamine (5 mL, 36 mmol) in dichloromethane (20 mL). The on was stirred for overnight (16 h) at room temperature. The on was washed with sodium bicarbonate solution (3 x 10 mL) and water (2 x 5 mL). After drying over sodium sulphate, the solvent was evaporated. The crude product was purified by flash chromatography (ethyl acetate/n-hexane: 2/98 to 3/97) to give di-tert—butyl N—trityl-L- glutamate (3.2 g, 88%) as a white foam. 0 o H3C CH3 H3c+o O+CH3 H3C HN\ CH3 di-tert—butyl N-trityl-L-glutamate 1H NMR (400 MHz, CDCls) 8 ppm 1.17 (s, 9H), 1.47 (s, 9H), 1.90-1.20 (m, 3H), 2.51 (ddd, 10 1H), 2.76 (br. d, 1H), 3.37 (br. s, 1H), 7.16-7.21 (m, 3H), 7.24-7.29 (m, 6H), 7.51 (br. d, 6H).
2. Alkylation A solution of di-terf—butyl N-trityl-L-glutamate (1.99 g, 1.85 mmol) in THF (50 mL) was cooled to -70°C and a 1.0 M solution of lithium bis(trimethylsilyl)amide 47 mL, 47 mmol) in THF was 15 added slowly (over a period of 20 min). The solution was stirred for 2 h at -70°C, and allyl bromide (1.44 g g, 11.9 mmol) was added drop wise at -70°C. After stirring for 1.5 h, the reaction mixture was quenched with saturated aqueous solution of NH4CI, and warmed up to room temperature, and concentrated under vacuum. The resulting aqueous solution was extracted with dichloromethane, the combined organic phase was washed with water and 20 was dried over sodium sulfate. After filtration, the solution was evaporated and the crude t was purified by flash chromatography (silica, ethyl acetate/n-hexane) to give the di- terf—butyl l-N-trityl-L-glutamate (1.01 g, 46%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers. o o H3C CH3 H3c+o O+CH3 H3C HN CH3 \Trt di-tert—butyl 4-allyl-N—trityl-L-glutamate 25 1H NMR (400 MHz, CDCls) 6 ppm 1.16 (s, 9H), 1.45 (s, 9H), 1.69-1.77 (m, 1H), 2.10-2.37 (m, 3H), 2.43-2.51 (m, 1H), 2.74 (br. d, 1H), 3.26-3.33 (m, 1H), 4.96-5.06 (m, 2H), 5.63-5.76 (m, 1H), 7.14-7.18 (m, 3H), 7.21-7.27 (m, 6H), .51 (m, 6H). MS (ES+) C35H43NO4I m/z 541 [M]+. Methods to separate diastereoisomers are known to person skilled in the art (e.g. chromatography s) allowing an access to pure the isomers (ZS/ZR) and (28/48) that can be r converted to isomerical pure compounds similar as described in the uent steps below. Borane tetrahydrofuran complex (1 M, 2.8 mL, 2.8 mmol) was added drop wise to a solution of di-terf—butyl 4-allyl-N-trityl-L-glutamate (1.00 g, 1.85 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred for 2 h at 0 °C and for 16 h at room temperature. The solution 10 was cooled to 0 °C. NaOH (1 M, 3 mL) and H202 (30% in water, 3 mL) were added drop wise. The e was stirred at 0 °C for 1 h. Water (5 mL) was added and the mixture was concentrated under reduced pressure. The s residue was extracted with ethyl acetate. The combined organic fraction was washed with brine, dried over sodium sulfate, filtrated and concentrated. The crude t was purified by flash chromatography (silica, 15 ethyl acetate/hexane) to afford di-terf—butyl 4-(3-hydroxypropyl)-N-trityl-L-g|utamate (0.46 g, 44%) as a mixture of (4S,4S)/(28,4R) diastereoisomers. o 0 H30 CH3 H3c+o O+CH3 H30 HN\ CH3 di-tert—butyl 4-(3-hyd roxypropyl)—N-trityl-L-glutamate 1H NMR (400 MHz, CDCls) 8 ppm 1.16 (s, 9H), 1.47 (s, 9H), 1.48-1.78 (m, 5H), 2.06-2.20 (m, 1H), 2.35-2.45 (m, 1H), 2.70-2.82 (m, 1H), .34 (m, 1H), 3.55-3.67 (m, 2H), 7.12-7.20 20 (m, 3H), 7.21-7.30 (m, 6H), 7.45-7.53 (m, 6H). MS (ES+) 035H45N05: m/z 560 [M]+. Methods to separate diastereoisomers are known to person skilled in the art (e.g. chromatography methods) allowing an access to pure the isomers (ZS/ZR) and (28/48) that 25 can be further converted to isomerical pure compounds similar as described in the subsequent steps below. Exam le com ounds of theinvention Precursor com ounds ll 30 Di-terf—but | 48 3- 2-na hth lsulfon lox ro l-N-trit l-L- lutamate Id and Di-terf— but I 4R 3- 2-na hth n lox ro l-N-trit l-L- lutamate lk At 0 °C triethylamine (0.68 mL, 4.90 mmol) and naphthalenesulfonyl chloride (0.370 g, 1.63 mmol) were added to a solution of di-tert—butyl 4-(3-hydroxypropyl)-N-trity|-L-g|utamate (0.457 g, 0.816 mmol) in dichloromethane (10 mL). The resulting e was stirred at 0 °C for 2 h and for 16 h at room temperature. The solution was concentrated and the crude product was purified by flash chromatography (silica, ethyl acetate/hexane) to afford di-tert— butyl 4-{3-[(2-naphthylsulfonyl)oxy]propyl}-N-trityl-L-glutamate (0.479 mg, 78%) as a mixture of (4S,4S)/(2S,4R) reoisomers. The isomers were separated by chiral HPLC (Chiralpak lC 5pm 250x30 mm, ethanol/methanol 1:1, 30 mL/min): f—butyl (4S)—4-{3-[(2-naphthylsulfonyl)oxy]propyl}-N-trityl-L-glutamate (Id): 80 mg, 13%, 10 di-terf—butyl (4R)—4-{3-[(2-naphthylsulfonyl)oxy]propyl}-N-trityl-L-glutamate (lk): 323 mg, 53%. o o H3C CH3 ch+0 5 H C = 3 J/ HN o—GCCH3H \Trt 3 o=s=o o o H3C CH3 ch+o O+CH3 H3C HN\ CH3 o=s=o di-tert—butyl (4R)—4-{3-[(2-naphthylsu|fony|)oxy]propy|}-N-trity|-L-glutamate (lk) 1H NMR (400 MHz, CDCIs) 8 1.12 (s, 9H), 1.27 (s, 9H), 1.50-1.70 (m, 5H), 2.00-2.10 (m, 1H), 15 2.22-2.32 (m, 1H), 2.74 (d, J = 8.8 Hz, 1H), 3.14-3.24 (m, 1H), 4.04 (t, J = 6.4 Hz, 2H), 7.10- 7.16 (m, 3H), 7.18-7.24 (m, 6H), .46 (m, 6H), 7.60-7.72 (m, 2H), 7.85 (dd, J = 1.6, 8.0 Hz, 1H), 7.93 (d, J: 8.0 Hz, 1H), 7.96-8.02 (m, 2H), 8.48 (d, J: 1.2 Hz,1H). MS (ES+) C45H51N078: m/z 750 [M]+. 1H NMR (400 MHz, CDCIs) 8 1.14 (s, 9H), 1.41 (s, 9H), 1.43-1.52 (m, 3H), .64 (m, 2H), 2.10 (ddd, 1H), .37 (m, 1H), 2.71 (br. d, 1H), 3.22 (td, 1H), 4.03 (t, 2H), 7.16 (d, 3H), 7.20-7.25 (m, 6H), 7.45-7.49 (m, 6H), 7.65 (ddd, 1H), 7.69 (ddd, 1H), 7.84 (dd, 1H), 7.93 (d, 1H), 7.76 (d, 2H), 7.99 (dd, 1H), 8.49 (d, 1H). MS (ES+) C45H51N078: m/z 750 [M]+. Di-terf—but l 48 3- 4-meth l hen lsulfon l ro l N-trit l-L- lutamate lm and Di-tert— but I 4R 3- 4-meth l hen lsulfon lox ro l-N-trit l-L- lutamate In 10 At 0 °C triethylamine L, 2.2 mmol) and 4-methylbenzenesulfonyl chloride (0.141 g, 0.74 mmol) were added to a solution of di-tert—butyl 4-(3-hydroxypropyl)-N-trityl-L-glutamate (0.239 g, 0.427 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at 0 °C for 2 h and for 16 h at room temperature. The solution was concentrated and the crude product was purified by flash chromatography (silica, ethyl acetate/hexane) to afford di-tert— 15 butyl 4-{3-{[(4-methylphenyl)sulfonyl)oxy]propyl}-N-trityl-L-glutamate (0.255 mg, 67%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers. The isomers were separated by chiral HPLC (Chiralpak AD-H 5pm 250x20 mm, hexane/2-propanol 9:1, 25 mL/min): di-terf—butyl (4S)—4-{3-{[(4-methylphenyl)sulfonyl]propyl}-N-trityl-L-glutamate (lm): 34 mg (11%) 20 f—butyl (4R)—4-{3-{[(4-methylphenyl)sulfonyl)oxy]propyl}-N-trityl-L-glutamate (In): 127 mg (42%). o 0 H30 CH3 ch+o O+CH3 H3C HN\ CH3 o=s=o di-tert-butyl -{3-{[(4-methy|phenyl)suIfonyl)oxy]propy|}-N-trityI-L-g|utamate (In) 1H NMR (400 MHz, CDCIs) 5 1.14 (s, 9H), 1.30 (s, 9H), 1.45-1.68 (m, 5H), 2.03-2.15 (m, 1H), 2.22-2.31 (m, 1H), 2.44 (s, 3H), 2.75 (ms, 1H), 3.21 (dd, 1H), 4.00 (t, 2H), 7.12-7.18 (m, 3H), 7.21-7.28 (m, 6H), 7.33 (d, 2H), 7.41-7.47 (m, 6H), 7.78 (d, 2H). 1H NMR (400 MHz, CDCIs) 5 1.15 (s, 9H), 1.42 (s, 9H), 1.48-1.65 (m, 5H), 2.10 (ddd, 1H), 2.34 (dt, 1H), 2.44 (s, 3H), 2.71 (br. s, 1H), 3.23 (br. s, 1H), 3.95 (t, 2H), 7.13-7.18 (m, 3H), 7.21-7.29 (m, 6H), 7.32 (d, 2H), .48 (m, 6H), 7.76 (d, 2H). 1 8F-fluorination of example compounds ll Radiolabelin of di-terT-but | 4R 3- 4-meth | hen Isulfon on r0 | N-trit |-L- glutamate (In) o o o 0 H30 CH3 ch+o O+CH3 HO OH H30 HN\ CH3 NH2 9 18': O=S=O (4R)—4-(3-fluoropropyl)—L-glutamic acid The radiolabeling was performed on a GE Tracerlab MX synthesizer. luoride (968 MBq) was trapped an anion exchange cartridge (QMA light, Waters). The activity was eluted with a solution of 5 mg fix and 1 mg potassium carbonate in 600 uL acetonitrile/water (1:1). The e was dried by heating under gentle nitrogen stream and vacuum. Drying was repeated after on of acetonitrile. 5.9 mg di-tert—butyl (4R)—4-{3-{[(4- methylphenyl)sulfonyl)oxy]propyl}-N-trityl-L-glutamate (In) in 1.5 mL acetonitrile were added and the mixture was heated at 120 °C for 5 min. After on of 2 mL HCI (2M), the mixture was heated for 5 min at 130 °C. 1.5 mL NaOH (4M) were added and the mixture was heated 10 for 5 min at 70 °C. The crude t was diluted with 2 mL HCI (2M) and water (up to 30 mL) and passed through two MCX cartridges (MCX plus, Waters). The cartridges were washed with water (30 mL) and the radiolabeled product was eluted from the MCX cartridges through a Hypercarb cartridge (Hypercarb 500 mg, Thermo ific) with 15 mL phosphate buffer (7 g Na2HPO4 2 H20; 6 g NaCl in 1 | H20) into the product vial to obtain 381 MBq (34% 15 do.) (4R)—4-(3-fluoropropyl)-L-g|utamic acid. The radiochemical purity was determined to be > 96% by radio-HPLC (Luna 5p 018(2); 250*4,6mm; 5p; Phenomenex; 12-100% acetonitrile in 0.01 M Na2HPO4; pre-column derivatization with Fluoraldehyde, o-Phthalaldehyde Reagent Solution; Thermo Scientific). Radiolabelin of di-tert—but | 48 3- 2-na hth lsulfon lox ro l-N-trit l-L- lutamate O 1% O=S=O O (4S)—4-(3-fluoropropyl)—L-glutamic acid The radiolabeling was performed on a GE Tracerlab MX synthesizer. [18F]Fluoride (2915 MBq) was trapped an anion exchange cartridge (QMA light, ). The activity was eluted with a solution of 3 mg kryptofix and 0.6 mg ium carbonate in 800 uL acetonitrile/water (1:1). The mixture was dried by heating under gentle nitrogen stream and vacuum. Drying was repeated after addition of itrile. 6 mg di-tert—butyl (4S)—4-{3-[(2- naphthylsulfonyl)oxy]propyl}-N-trityl-L-glutamate (Id) in 1.5 mL acetonitrile were added and the mixture was heated at 130 °C for 5 min. After addition of 2 mL HCI (2M), the mixture was heated for 10 min at 120 °C. The crude product was diluted with water (up to 30 mL) and passed through two MCX cartridges (MCX plus, Waters). The cartridges were washed with 10 water (30 mL) and the radiolabeled product was eluted from the MCX cartridges through a Hypercarb cartridge (Hypercarb 500 mg, Thermo Scientific) with 10 mL phosphate buffer (7 g Na2HPO4 2 H20; 6 g NaCl in 1 l H20) into the product vial to obtain 1168 MBq (40% n.d.c.) (4S)—4-(3-f|uoropropy|)-L-g|utamic acid. The hemical purity was determined to be > 96% by radio-HPLC > 95% by radio-HPLC (Advanced Chromatography Technologies ACE 5 15 C18 250x4.6mm; 2-100% B in 0.04M Na2HPO4; B: 45% acetonitrile, 45% methanol, 10% water; pre-column derivatization with o—Phthalaldehyde Reagent Solution; Agilent). Radiolabelin of di-terf—but l 4R 3- 2-na hth lsulfon lox ro l-N-trit l-L- lutamate O -(3-fluoropropyl)—L-glutamic acid The radiolabeling was performed on a GE Tracerlab MX synthesizer. [18F]Fluoride (9400 MBq) was d an anion exchange cartridge (QMA light, Waters). The activity was eluted with a solution of 3 mg kryptofix and 0.6 mg potassium carbonate in 800 uL acetonitrile/water 25 (1:1). The mixture was dried by heating under gentle nitrogen stream and vacuum. Drying was repeated after addition of itrile. 6 mg di-tert—butyl (4R)—4-{3-[(2- naphthylsulfonyl)oxy]propyl}-N-trityl-L-glutamate (lk) in 1.5 mL acetonitrile were added and the mixture was heated at 130 °C for 5 min. After on of 2 mL HCI (2M), the mixture was heated for 10 min at 120 °C. The crude product was d with water (up to 30 mL) and 30 passed h two MCX cartridges (MCX plus, Waters). The cartridges were washed with water (30 mL) and the radiolabeled product was eluted from the MCX cartridges through a Hypercarb cartridge (Hypercarb 500 mg, Thermo Scientific) with 10 mL ate buffer (7 g Na2HPO4 2 H20; 6 g NaCl in 1 l H20) into the product vial to obtain 5100 MBq (54% n.d.c.) (4R)(3-f|uoropropyl)—L-g|utamic acid. The radiochemical purity was determined to be > 96% by radio-HPLC > 95% by radio-HPLC (Advanced tography Technologies ACE 5 C18 250x4.6mm; 2-100% B in 0.04M Na2HPO4; B: 45% acetonitrile, 45% methanol, 10% water; pre-column derivatization with o-Phthalaldehyde Reagent Solution; Agilent). tautomers, diastereomers, enantiomers, stereoisomers, mixtures thereof, and le salts thereof.
2. The compound according to claim 1 wherein
4. nd according to any one of claims 1 to 3 selected from the list below WO 50204 Di-tert-butyl (4S){3-[(bipheny|—4-y|suIfonyl)oxy]propy|}-N-trityI-L-glutamate H3C O 0 E CH3 Di-tert-butyl (4S)—4-{3-[(2-naphthy|suIfonyl)oxy]propy|}-N-trityI-L-glutamate Di-tert-butyl (4S)—4-{3-[(1-naphthylsuIfonyl)oxy]propy|}-N-trityI-L-glutamate t-butyl (4S)—4-{3-[(quinolin-8—ylsuIfonyl)oxy]propy|}-N-trityI-L-glutamate CH O O CH H3CX3 J<3CH3 H3C O CH 5 C' Tetra-tert-butyl (28,48,2'S,4'S)—2,2'-[bipheny|—4,4'-diylbis(suIfonyloxypropane-3,1-diy|)]bis[4- (tritylamino)pentanedioate] 2012/057884 Di-tert-butyl (4S)—4-[3-({[4-nitro—3-(trifluoromethyl)pheny|]suIfony|}oxy)propyl]—N-trity|—L- glutamate di-tert-butyl (4S)—4-(3-{[(4-methylphenyl)sulfonyl]oxy}propy|)-N-trity|-L-glutamate di-tert-butyl (4R){3-[(2-naphthylsulfonyl)oxy]propyl}-N-trityl-L-glutamate CH 0 H. H30 3 jéCHs H30 0 0 CH3
5. A compound of Formula I or la according to any one of claims 1 to 4 in the solid form.
6. A method for obtaining compounds of formula I comprising the step: - ylation of compound of Formula II with a ylhalide or sulfonyl anhydride having both a suitable substituent A, Formula II Formula | 0 CH3 wherein R1 is triphenylmethyl (Trityl), A is selected from the group: a) Monocyclic aryl, b) Bicyclic aryl, c) , d) Monocyclic heteroaryl, and e) Bicyclic aryl optionally, A is bearing one or more substituents selected from the group comprising: a) Halogen, b) Nitro, c) Alkyl, d) oromethyl, and e) Z, wherein Z is R1 is triphenylmethyl (Trityl), and # indicates the position of the bond to A.
7. The method according to claim 6, wherein the sulfonylhalide is sulfonylchloride.
8. The method according to claim 6 or 7 for obtaining a compound with (2S,4S)‐configuration (compound of a Ia) wherein R1 and A is as defined in claims 1 or 2.
9. A method for obtaining compounds of formula IV‐F18 comprising the steps ‐ Reacting compound of Formula I according to claim 1 with a 18F‐ Fluorination agent to obtain a compound of formula III‐F18, and ‐ Deprotecting the obtained compound of formula III‐F18 for obtaining a compound of formula IV‐F18, wherein compound of formula III‐F18 is Formula 8 wherein R1 is triphenylmethyl (Trityl), and compound of formula IV‐F18 is Formula IV‐F18.
10. The method according to claim 9 wherein the obtained compound is a compound with (2S,4S)‐configuration (formula 8) and comprising the steps - Reacting compound of Formula Ia according to claim 3 with a 18F‐ Fluorination agent to obtain a compound of formula llla‐F18, and - Deprotecting the obtained compound of formula llla‐F18 for obtaining a nd of a IVa‐F18, wherein compound of formula 18 is Formula llla‐F18 R1 is triphenylmethyl (Trityl) and compound of formula 1Va‐F18 is Formula IVa‐F18.
11. A compound of formula II wherein R1 is triphenylmethyl (Trityl) and tautomers, diastereomers, enantiomers, stereoisomers, mixtures thereof, and suitable salts thereof.
12. The compound according to claim 11 with (2S,4S)‐configuration (compound of formula lla) wherein R1 is triphenylmethyl (Trityl) corresponding to di‐tert‐butyl (48)‐4‐(3‐hydroxypropyl)‐ N‐trityl‐L‐glutamate.
13. A compound of a III‐F a III‐F wherein R1 is triphenylmethyl (Trityl), F means fluorine atom, and tautomers, reomers, enantiomers, stereoisomers, mixtures thereof and suitable salts thereof.
14. The compound according to claim 13, n F is 18F or 19F.
15. The compound according to claim 13 or 14 with (2S,4S)‐configuration (compound of formula Illa‐F)
16. A ition comprising a compound of formula I, Ia, II, lla, III‐F, llla‐F, or llla‐F18: wherein A is selected from the group: a) Monocyclic aryl, b) Bicyclic aryl, c) Biaryl, d) Monocyclic heteroaryl, and e) Bicyclic heteroaryl optionally, A is bearing one or more substituents selected from the group comprising: a) Halogen, b) Nitro, c) Alkyl, d) Trifluoromethyl, and e) Z, wherein Z is R1 is triphenylmethyl (Trityl), and # tes the position of the bond to A; and tautomers, reomers, enantiomers, stereoisomers, mixtures f, and suitable salts thereof.
17. A kit comprising one vial or more than one vial comprising a predetermined quantity of compounds of Formula I: wherein A is selected from the group: a) Monocyclic aryl, b) Bicyclic aryl, c) Biaryl, d) Monocyclic heteroaryl, and e) Bicyclic heteroaryl optionally, A is g one or more substituents selected from the group comprising: a) Halogen, b) Nitro, c) Alkyl, d) Trifluoromethyl, and e) Z, wherein Z is R1 is triphenylmethyl (Trityl), and # indicates the on of the bond to A; and tautomers, diastereomers, enantiomers, stereoisomers, mixtures thereof, and suitable salts thereof.
18. A compound prepared by the method of any one of claims 6 to 10.
19. A compound according to claim 1, substantially as herein described or exemplified.
20. A compound ing to claim 5, ntially as herein described or exemplified.
21. A method according to claim 6, ntially as herein described or exemplified.
22. A compound according to claim 11, substantially as herein described or exemplified.
23. A compound according to claim 13, substantially as herein described or exemplified.
24. A composition according to claim 16, substantially as herein described or exemplified.
25. A kit ing to claim 17, substantially as herein described or exemplified.
26. A compound according to claim 18, substantially as herein described or exemplified.