Novel uses of triazolo[4,5-d]pyrimidine derivatives

Abstract

Triazolo[4,5-d]pyrimidine derivatives of formula (I) for use in the prognosis and / or diagnosis of bacterial infection in a host mammal, and methods of imaging thereof. 1 is a C optionally substituted by one or more halogen atoms 3-5 alkyl; R 2 is a phenyl group optionally substituted by one or more halogen atoms; R 3 and R 4 are each hydroxyl; R is XOH, where X is CH, OCHCH, or a bond, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, provided that when X is CH or a bond, then R 1 is not propyl; X is CH2 and R 1 is CH2CH2CF3, butyl or pentyl, R 2 The phenyl group in must be substituted with fluorine; X is OCH2CH2, and R 1 is propyl, R 2 The phenyl group in the formula (I) must be substituted with fluorine.

Description

[Technical Field]

[0001] The present invention relates to triazolo[4,5-d]pyrimidine derivatives for use in the in vivo prognosis and / or diagnosis of bacterial infections, particularly deep-seated bacterial infections, in a host mammal. The present invention also relates to methods for imaging said bacterial infections, and to the use of triazolo[4,5-d]pyrimidine derivatives in the in vitro prognosis and / or diagnosis of bacterial infections. [Background technology]

[0002] Introduction Bacterial infections, especially when deep-seated infections are present, are a major cause of morbidity and mortality.

[0003] Deep-seated infections are difficult to diagnose from other causes of inflammation. Current practice relies on biopsies, blood and urine sample analysis, or radiological techniques, such as magnetic resonance imaging (MRI), X-rays, ultrasound (US), and X-ray computed tomography (CT), which can identify the site of infection and detect morphological changes associated with infection, host response, or both. Unfortunately, such morphological changes may not be distinct from inflammation or cancerous tumors. Furthermore, these morphological changes may not be detectable in the early stages of infection and, if present, remain nonspecific.

[0004] Deep-seated infections can also be identified using tracers labeled with radioactive elements, called radioactive markers. Radioactive markers, also called radioactive tracers, can be detected by nuclear imaging techniques such as single photon emission computed tomography (SPECT) or positron emission tomography (PET). Examples of radioactive tracers include: 18 F-fluorodeoxyglucose PET, 67 Ga-citrate SPECT or radiolabeled leukocyte SPECT, but these are not specific for bacterial infection and cannot distinguish between infection and sterile inflammation or cancer.

[0005] Therefore, there is an urgent need in the art for new tracers for use in the prognosis or diagnosis of bacterial infections, especially deep-seated infections in mammalian hosts. Bacteria-specific and highly sensitive tracers that are non-toxic, affordable, widely available, and easily and rapidly prepared are needed.

[0006] Summary of the Invention Surprisingly, we have found that triazolo[4,5-d]pyrimidine derivatives or compositions thereof can be used as tracers in the prognosis and / or diagnosis of bacterial infection in host mammals. Because triazolo[4,5-d]pyrimidine derivatives rapidly and non-invasively target early infections, they are advantageous for distinguishing infection from sterile inflammation or cancer. Triazolo[4,5-d]pyrimidine derivatives are also advantageous for diagnosing or predicting the prognosis of a wide range of bacteria, both Gram-positive and Gram-negative.

[0007] Triazolo[4,5-d]pyrimidine derivatives can be taken up by bacterial cells and can therefore be used as tracers for the in vivo or in vitro prognosis and / or diagnosis of bacterial infections.

[0008] Detailed Description In one aspect, the present invention provides a triazolo[4,5-d]pyrimidine derivative of formula (I) for use in the in vivo prognosis and / or diagnosis of bacterial infection in a host mammal.

[0009] In another aspect, the present invention provides the use of a triazolo[4,5-d]pyrimidine derivative of formula (I) in the in vitro prognosis and / or diagnosis of bacterial infections.

[0010] The term "bacterial infection" refers to, for example, pneumonia, sepsis, endocarditis, osteomyelitis, meningitis, urinary tract, skin, and soft tissue infections, but also cardiac implant-associated infective endocarditis, prosthetic valve endocarditis, or periprosthetic joint infections, which occur in 1 or 2 percent of joint replacement surgeries.

[0011] Bacterial infections may be caused by one or more of the following bacteria: Staphylococcus aureus (S. aureus), Staphylococcus epidermidis (S. epidermidis), Enterococcus faecalis (E. faecalis), Enterococcus faecium (E. faecium), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), glycopeptide-intermediate Staphylococcus aureus (GISA), coagulase-negative Staphylococci (CoNS), vancomycin-resistant enterococci (VRE), beta-hemolytic Streptococcus agalactiae (group B streptococcus, GBS) or other streptococci belonging to the gram-positive bacteria, or by Acinetobacter baumannii, Pseudomonas aeruginosa, belonging to the gram-negative bacteria. aeruginosa, carbapenem-resistant Pseudomonas aeruginosa, Enterobacteriaceae, and third-generation cephalosporin-resistant Enterobacteriaceae (Klebsiella pneumoniae, Escherichia coli, Enterobacter spp, Serratia spp, Proteus spp, Providencia spp, and Morganella spp).

[0012] The term diagnosis as used herein refers to identifying a bacterial infection in a host mammal.

[0013] The term prognosis as used herein refers to determining the intensity of a bacterial infection in a host mammal at any stage, particularly at an early stage.

[0014] The term host mammal as used herein preferably refers to humans, but also to animals.

[0015] In certain embodiments, the triazolo[4,5-d]pyrimidine derivative of Formula (I) comprises a detectable marker.

[0016] In another particular embodiment, the triazolo[4,5-d]pyrimidine derivative of Formula (I) is linked to a detectable marker.

[0017] As used herein, the term "detectable marker" refers to a marker that is capable of being detected and thus indicates the presence of a triazolo[4,5-d]pyrimidine derivative: -directly, e.g. one atom of a derivative, 2 H, 3 H, 13 F, 18 F, 19 F, 11 C. 13 C. 14 C. 75 Br, 76 Br, 120 I, 123 I, 124 I, 125 I, 131 I, 15 O. 13 N, 78 Br and the like; preferably, one halogen atom is substituted by one radioisotope marker selected from the group 13 F, 18 F, 19 F, 75 Br, 76 Br, 120 I, 123 I, 124 I, 125 I, 131 I, 78 Br, etc., as a radiolabeled triazolo[4,5-d]pyrimidine derivative; or -Directly, derivatives 99 Tc, 63 Ga, 67 Ga, 111 as a radiolabeled triazolo[4,5-d]pyrimidine derivative, optionally conjugated to a radioactive marker such as In; or - refers to any type of tag that allows detection indirectly, for example, via a transporter containing a signal amplifier. The triazolo[4,5-d]pyrimidine derivative is then chemically bound to the transporter, allowing the derivative to be considered a sensor of bacterial infection.

[0018] The term "signal amplifier" as used herein refers to any substance that amplifies the signal return in a bacterially infected tissue or implant.

[0019] For example, a signal amplifier may enhance the reflection, refraction, scattering, transmission or attenuation of ultrasound waves in US imaging tomography of bacterially infected tissue or implants; or may enhance the resonance of different hydrogen sequences in response to radio frequency pulses emitted by a magnetic field in magnetic resonance imaging of bacterially infected tissue or implants; or may enhance the proportion of X-rays absorbed or scattered by bacterially infected tissue or implants in X-ray computed tomography (CT).

[0020] As used herein, the term "transporter" refers to an entity that acts as a signal amplifier or into which a signal amplifier can be incorporated, such as, for example, a micelle, a microsphere, a liposome, a polymer particle, a nanosphere, a nanosuspension, a nanoemulsion, a nanocapsule, etc.

[0021] Triazolo[4,5-d]pyrimidine derivatives that contain a detectable marker via a radioisotope or that are bound to a detectable marker either via a complex with a detectable marker or via a transporter that contains a detectable marker are also referred to below as detectable triazolo[4,5-d]pyrimidine derivatives.

[0022] In certain embodiments, the detectable marker is a signal amplifier that indirectly binds to a triazolo[4,5-d]pyrimidine derivative, with the detection method used depending on the nature of the marker.

[0023] Triazolo[4,5-d]pyrimidine derivatives can be used, for example, with gadolinium (e.g., 64 The Gd chelate may be bound to a signal amplifier such as a Gd chelate. The Gd chelate may be ionic (e.g., meglumine or sodium salt) or non-ionic. Iron oxides can also be used as MRI signal amplifiers. For example, manganese-doped superparamagnetic iron oxide nanoparticles may be used to form ultrasensitive MRI contrast agents. Such Mn-SPIO nanoparticles then self-assemble into clusters in micelles that are detectable by MRI. Other MRI signal amplifiers include manganese chelates, iron-platinum (FePt) alloy nanocrystals, manganese ferrite (MnO-Fe2O3) nanocrystals, or iron oxide nanoparticles doped with other metals such as Co-Fe2O3 or NiO-Fe2O3.

[0024] The triazolo[4,5-d]pyrimidine derivatives may also be conjugated to signal amplifiers such as microbubbles used in contrast-enhanced ultrasound imaging (US).

[0025] The triazolo[4,5-d]pyrimidine derivatives may also be combined with signal enhancers, also called contrast agents, containing iodine or barium for X-ray computed tomography (CT). The contrast agent must increase the absolute CT attenuation difference between the target bacterial infection and the surrounding tissue. Examples of contrast agents suitable for X-ray computed tomography include iohexol (Omnipaque™, GE Healthcare); iopromide (Ultravist™, Bayer Healthcare); iodixanol (Visipaque™, GE Healthcare); ioxaglate (Hexabrix™, Mallinckrodt Imaging); iothalamic acid (Cysto-Conray II™, Mallinckrodt Imaging); and iopamidol (Isovue™, Bracco Imaging).

[0026] In another specific embodiment, the detectable marker is an isotope, and triazolo[4,5-d]pyrimidine derivatives can be used as tracers in the detection method depending on the nature of the marker.Therefore, the triazolo[4,5-d]pyrimidine derivatives that contain at least one detectable isotope can be detected by, for example, using beta, gamma, positron or X-ray imaging, where beta or gamma radiation is provided by the appropriate isotope and detected at the appropriate wavelength.

[0027] Triazolo[4,5-d]pyrimidine derivatives containing at least one detectable isotope can be used, for example, in magnetic resonance spectroscopy (MRS) or magnetic resonance imaging (MRI), X-ray computed tomography (CT), positron emission tomography (PET), and single photon emission computed tomography (SPECT).

[0028] Detectable triazolo[4,5-d]pyrimidine derivatives can be isotopically modified for MRS / MRI by well-known organic chemistry techniques. 19 F or 13 C or a combination thereof.

[0029] Other detectable triazolo[4,5-d]pyrimidine derivatives are also available for PET applications. 19 F, 11 C. 75 Br, 76 Br or 120 I or a combination thereof.

[0030] Other detectable triazolo[4,5-d]pyrimidine derivatives have also been used for PET in vivo imaging. 18 F or 11C or a combination thereof and can be prepared as described by Bengt Langstrom in Acta ChemicaScandinavia 53:651-669 (1999) or Journal of Nuclear Medicine 58(7):1094-1099 (2017), or by AMJ Paans at https: / / cds.cern.ch / record / 1005065 / files / p363.pdf.

[0031] Other detectable triazolo[4,5-d]pyrimidine derivatives are available for SPECT imaging. 123 I and 131 I and can be prepared as described by Kulkarni in Int. J. Rad. Appl. & Inst (part B) 18:647 (1991).

[0032] Other detectable triazolo[4,5-d]pyrimidine derivatives are also detectable with technetium-99m ( 99m Tc), 123 I and 111 Appropriately radiolabeled triazolo[4,5-d]pyrimidine derivatives can be easily prepared by those skilled in the art using techniques well known in the art, as described by Zhuang in Nuclear Medicine & Biology 26(2):217-24 (1999) or by Kulkarni in Nuclear Medicine & Biology 18(6):647-654 (1991) or technical reports 466 published by the International Atomic Energy Agency in 2008.

[0033] Triazolo[4,5-d]pyrimidine derivatives in which one or more atoms are substituted with a radionuclide or isotope can be used as radioactive tracers to examine cells, tissues or body fluids of a host mammal and identify the presence and severity of bacterial infection in the host, for example, on the surface of a prosthetic valve.

[0034] As used herein, the term "host mammal" preferably refers to a human, but also to animals.

[0035] The term triazolo[4,5-d]pyrimidine derivative refers to a compound of the following formula (I):

[0036] [ka] [In the formula, R 1 is a C optionally substituted by one or more halogen atoms 3-5 alkyl; R 2 is a phenyl group optionally substituted by one or more halogen atoms; R 3 and R 4 are each hydroxyl; R is XOH, where X is CH, OCHCH, or a bond, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, provided that when X is CH or a bond, then R 1 is not propyl; X is CH2 and R 1 is CH2CH2CF3, butyl or pentyl, R 2 The phenyl group in must be substituted with fluorine; X is OCH2CH2, and R 1 is propyl, R 2 The phenyl group in the formula (I) must be substituted with fluorine.

[0037] Alkyl groups, whether alone or part of another group, are straight-chained and fully saturated.

[0038] In some embodiments, R 1 is a C optionally substituted by one or more fluorine atoms 3-5 It may represent alkyl. Preferably, R 1 is 3,3,3-trifluoropropyl, butyl or propyl.

[0039] In some embodiments, R 2 may represent phenyl or phenyl substituted by one or more halogen atoms. Preferably, R 2 is phenyl substituted by one or more fluorine atoms. Most preferably, R 2 is 4-fluorophenyl or 3,4-difluorophenyl.

[0040] In some embodiments, R may represent XOH, where X is CH2, OCH2CH2, or a bond; preferably, R is OH or OCH2CH2OH.

[0041] The most preferred triazolo[4,5-d]pyrimidine derivatives are R 2 represents 4-fluorophenyl or 3,4-difluorophenyl and / or R represents OCH2CH2OH.

[0042] Triazolo[4,5-d]pyrimidine derivatives are well known compounds and can be obtained by the method described in US Pat. No. 6,525,060 (incorporated herein by reference) (described in column 3, line 26 to column 8, line 14).

[0043] Preferred triazolo[4,5-d]pyrimidine derivatives are those in which R represents OH or OCHCHOH and / or R 2 represents 4-fluorophenyl or 3,4-difluorophenyl.

[0044] The most preferred triazolo[4,5-d]pyrimidine derivatives are: (1R-(1α,2α,3β(1R* ,2 * ),5β))-3-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-((3,3,3-trifluoropropyl)thio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxy)cyclopentane-1,2-diol; (1S-(1α,2α,3β(1R * ,2 * ),5β))-3-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol; (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol; (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(4-fluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol or a pharmaceutically acceptable salt or solvate thereof, or a solvate thereof or a solvate of such a salt.

[0045] The most preferred triazolo[4,5-d]pyrimidine derivatives for prognostic and / or diagnostic use have the formula (II):

[0046] [ka] or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.

[0047] Another most preferred triazolo[4,5-d]pyrimidine derivative for prognostic and / or diagnostic use has the formula (III):

[0048] [ka] or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.

[0049] In some embodiments, one atom of the triazolo[4,5-d]pyrimidine derivative of Formula (I) is 3 H, 13 F, 18 F, 19 F, 11 C. 13 C. 14 C. 75 Br, 76 Br, 120 I, 123 I, 124 I, 125 I, 131 I, 15 O. 13 N, 78 Br.

[0050] In some embodiments, one halogen substituent of the triazolo[4,5-d]pyrimidine derivative of Formula (I) is 18 F or 123 It can be I.

[0051] In some embodiments, one halogen substituent of the triazolo[4,5-d]pyrimidine derivative of Formula (I) is 18 It can be F.

[0052] In some embodiments, R in the triazolo[4,5-d]pyrimidine derivative of Formula (I) 2 One halogen substituent of 18 It can be F.

[0053] In a further aspect, the present invention provides a pharmaceutical composition comprising a triazolo[4,5-d]pyrimidine derivative of formula (I) and a pharmaceutically acceptable excipient for use in the in vivo diagnosis and / or prognosis of a bacterial infection in a host mammal.

[0054] In yet another aspect, the present invention provides the use of a pharmaceutical composition comprising a triazolo[4,5-d]pyrimidine derivative of formula (I) and a pharmaceutically acceptable excipient in the in vitro prognosis and / or diagnosis of bacterial infection.

[0055] The pharmaceutical composition may be a physiologically compatible dry powder or liquid composition. In some embodiments, the pharmaceutically acceptable excipients may be auxiliary substances, preservatives, solvents, and / or viscosity adjusting agents.

[0056] By solvent is meant any suitable physiologically compatible solvent, such as, for example, water, saline or any other physiological solution, ethanol, glycerol, oils such as vegetable oils, or mixtures thereof, etc. By viscosity modifier is meant, for example, sugar polymers such as carboxymethylcellulose, polysaccharides such as saccharin, etc.

[0057] In some embodiments, the triazolo[4,5-d]pyrimidine derivative or pharmaceutical composition thereof containing a detectable marker and used as a radiotracer can be administered locally or systemically by inhalation, ingestion, or injection in a dose appropriate for the selected imaging device. Administration can be oral, parenteral, topical, rectal, nasal, or vaginal.

[0058] Parenteral means subcutaneous, intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular and the like.

[0059] The dosage level for administration to a host mammal will depend on its age, weight, general health, sex, time of administration, dosage form, etc., and will be known to those skilled in the art. Dose levels can vary between 0.001 μg / kg / day and 10,000 mg / kg / day, depending on the imaging technique selected.

[0060] In other embodiments, a triazolo[4,5-d]pyrimidine derivative or a pharmaceutical composition thereof containing a detectable marker and used as a radioactive tracer can be added to a sample obtained from a host mammal in an effective amount appropriate for the selected imaging device.

[0061] A sample obtained from a host mammal refers to any sampling of cells, tissues, or bodily fluids from which bacterial infection can be determined. Examples of such samples include blood, lymph, urine, biopsy, or bone marrow.

[0062] The sample may also refer to an implant on whose surface a bacterial infection can be determined.

[0063] By implant is meant any implantable foreign object intended for clinical use in a host mammal, such as an artificial joint, a pacemaker, an implantable cardioverter defibrillator, an intravascular or urinary catheter, a stent, including a coronary stent, an artificial heart valve, an intraocular lens, a dental implant, etc.

[0064] In yet another aspect, the present invention also provides a method for imaging a bacterial infection in a host mammal, comprising administering to the host mammal a detectable amount of a triazolo[4,5-d]pyrimidine derivative.

[0065] In a further aspect, the present invention also provides the use of a triazolo[4,5-d]pyrimidine derivative in an in vitro method for imaging bacterial infection.

[0066] In some embodiments, the imaging method may include the following steps: (a) administering to a host mammal a triazolo[4,5-d]pyrimidine derivative of formula (1) or a pharmaceutical composition containing a detectable amount of the detectable marker; or adding to a sample obtained from the host mammal a triazolo[4,5-d]pyrimidine derivative of formula (1) or a pharmaceutical composition containing a detectable amount of the detectable marker; and (b) tracking the detectable triazolo[4,5-d]pyrimidine derivative by imaging techniques such as, for example, magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET), positron emission tomography with computed tomography, positron emission tomography with magnetic resonance; and displaying an image of the bacterial infection.

[0067] In certain embodiments, the imaging technique is positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0068] The use of detectable triazolo[4,5-d]pyrimidine derivatives of formula (I) or compositions thereof is useful not only to indicate bacterial infection, but also to monitor the treatment of bacterial infection in a host. Indeed, improved knowledge of the severity of bacterial infection may further refine appropriate treatments and reduce the likelihood of bacterial resistance developing.

[0069] If a detectable triazolo[4,5-d]pyrimidine derivative of formula (I) or a composition thereof is administered prior to treatment of an infection (e.g., by administration of an antibiotic) or added to a sample obtained from a host, it will be possible to administer a precise effective amount of the antibiotic to the host.

[0070] In yet another aspect, the present invention also provides a tracer, preferably a positron emission tomography (PET) tracer or a single photon emission computed tomography (SPECT) tracer, comprising a triazolo[4,5-d]pyrimidine derivative of formula (I) for the in vivo prognosis and / or diagnosis of bacterial infections or the in vitro prognosis and / or diagnosis of bacterial infections.

[0071] In some embodiments, the tracer may be an imaging tracer. In some embodiments, the tracer may comprise a pharmaceutical composition.

[0072] The present invention will now be described with reference to the following figures of the accompanying drawings, which are not intended to limit the scope of the invention as claimed: [Brief explanation of the drawings]

[0073] [Figure 1] FIG. 1 shows a reaction scheme illustrating the synthesis of the labeled precursor detailed in step (i) of Example 1; and [Figure 2] FIG. 2 shows a reaction scheme illustrating the synthesis of a further label precursor detailed in step (ii) of Example 1.

[0074] The present invention is further described in the following examples, which are not intended to limit the scope of the claimed invention in any way. Example 1

[0075] Detectable Markers 18 as F-containing triazolo[4,5-d]pyrimidine derivatives 18Preparation of F-triafluosyl. i) Synthesis of the initial labeled precursor shown in Figure 1: (3-((3aS,4R,6S,6aR)-6-(2-((tert-butoxycarbonyl)oxy)ethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)((1R,2S)-2-(3-fluoro-4-(trimethylstannyl)phenyl)cyclopropyl)tert-butyl carbamate (5). In the first step (i), 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (1) is obtained by the reaction of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine, which is carried out in acetonitrile at 110° C. in a sealed vessel. The next step (ii) consists of the ring closure reaction (step (ii)) of intermediate 1 by diazotization with sodium nitrite in acetic acid at temperatures between 5°C and 20°C to yield 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (2). In step (iii), 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(4-bromo-3-fluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (3) can be obtained by nucleophilic substitution of the chlorine atom of intermediate (2) with 2-(4-bromo-3-fluorophenyl)cyclopropanamine hydrochloride, for example, at a temperature of 20°C. The sensitive amino and hydroxyl functionalities of (3) are then protected with tert-butoxycarbonyl groups (step (iv)), for example, by reacting (3) with di-tert-butyl dicarbonate in tetrahydrofuran at a temperature of 20° C. to give tert-butyl ((1R,2S)-2-(4-bromo-3-fluorophenyl)cyclopropyl)(3-((3aS,4R,6S,6aR)-6-(2-((tert-butoxycarbonyl)oxy)ethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)carbamate (4). In the next step (step (v)), the bromine atom of (4) is nucleophilically substituted with the trimethylstannyl group using hexamethyldistannane in the presence of tetrakis(triphenylphosphine)palladium(0) as a catalyst to activate the labeled position, giving tert-butyl (3-((3aS,4R,6S,6aR)-6-(2-((tert-butoxycarbonyl)oxy)ethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)((1R,2S)-2-(3-fluoro-4-(trimethylstannyl)phenyl)cyclopropyl)carbamate (5).

[0076] The intermediate products (1) to (5) shown in FIG. 1 are hereinafter referred to as intermediates (1) to (5). Intermediate (1) is obtained as follows: a mixture of 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (1.0 g, 4.2 mmol), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (1.17 g, 5.4 mmol) and triethylamine (0.6 mL, 4.2 mmol) in acetonitrile (10 mL) is introduced into a sealed vessel and heated at 110° C. overnight. After evaporation of the solvent, the residue is purified by silica gel column chromatography. Yield: 77%. Melting point: 112~114℃. 1 H NMR (CDCl3) δ 1.03 (t, J=7.4 Hz, 3H, SCH2CH2CH3), 1.26 (s, 3H, CH3), 1.43 (s, 3H, CH3), 1.75 (m, 2H, SCH2CH2CH3), 1.92 (d, J=14.5 Hz, 1H, 5'-Ha), 2.28 (ddd, J=14.5 Hz / 5.9 Hz / 4.4 Hz, 1H, 5'-Hb), 2.59 (bs, 1H, OH), 2.99 (ddd, J=13.4 Hz / 8.2 Hz / 6.4 Hz, 1H, SCHa), 3.14 (ddd, J=13.5 Hz / 8.2 Hz / 6.4 Hz, 1H, SCHb), 3.38 (bs, 2H, NH2), 3.60 (ddd, J=9.9 Hz / 6.1 Hz / 2.6 Hz, 1H, OCHa), 3.70 (ddd, J=9.9 Hz / 5.8 Hz / 2.5 Hz, 1H, OCHb), 3.79 (m, 2H, OCH2CH2OH), 3.97 (d, J=4.1 Hz, 1H, 4'-H), 4.53 (dd, J=5.4 Hz / 1.2 Hz, 1H, 3a'-H), 4.59 (m, 1H, 6'-H), 4.61 (dd, J=5.5 Hz / 1.8 Hz, 1H, 6a'-H), 6.17 (d, J=8.4 Hz, 1H, NH). 13C NMR (CDCl3) δ 13.5, 23.2, 23.8, 26.2, 32.5, 33.2, 56.8, 61.9, 70.4, 82.8, 84.5, 85.3, 110.3, 116.9, 144.5, 154.4, 162.0.

[0077] Intermediate (2) is obtained as follows: To a solution of (1) (1.0 g, 2.4 mmol) in acetic acid (10 mL) cooled on an ice bath, NaNO (225 mg, 3.2 mmol) is added. The resulting mixture is allowed to reach room temperature within 1 h, and then water (40 mL) is added. The resulting mixture is extracted with ethyl acetate (3 × 50 mL), the combined organic layers are dried over MgSO, and the solvent is evaporated to give an oily residue. Yield: 94%. Melting point: oil. 1 H NMR (CDCl3) δ 1.09 (t, J=7.4 Hz, 3H, SCH2CH2CH3), 1.37 (s, 3H, CH3), 1.55 (s, 3H, CH3), 1.83 (h, J=7.4 Hz, 2H, SCH2CH2CH3), 2.14 (t, J=6.0 Hz, 1H, OH), 2.54 (m, 1H, 5'-Ha), 2.70 (m, 1H, 5'-Hb), 3.21 (t, J=7.2 Hz, 2H, SCH2CH2CH3), 3.49-3.65 (m, 4H, OCH2CH2OH), 4.05 (m, 1H, 4'-H), 4.88 (d, J=6.3 Hz, 1H, 3a'-H), 5.21 (td, J=7.4 Hz / 6.4 Hz / 2.5 Hz, 1H, 6'-H), 5.53 (dd, J=6.3 Hz / 2.1 Hz, 1H, 6a'-H). 13 C NMR (CDCl3) δ13.6, 22.3, 24.5, 26.8, 33.9, 35.9, 61.8, 63.4, 70.7, 82.9, 83.6, 84.0, 112.4, 132.2, 150.7, 153.4, 171.8.

[0078] Intermediate (3) was obtained by mixing (2) (0.5 g, 1.16 mmol), 2-(4-bromo-3-fluorophenyl)cyclopropanamine hydrochloride (0.3 g, 1.16 mmol) with triethylamine (0.21 mL, 1.45 mmol) in acetonitrile (10 mL) and reacting the resulting mixture at room temperature for 2 hours. After evaporating the solvent, the residue was purified by silica gel column chromatography. Yield: 98%. Melting point: 122~124℃. 1H NMR (DMSO-d6) δ 0.82 (t, J = 7.4 Hz, 2.4H, SCH2CH2CH3 major), 0.99 (t, J = 7.3 Hz, 0.6H, SCH2CH2CH3 minor), 1.26 (s, 3H, CH3), 1.42 (m, 1H, 3'-Ha), 1.48 (s, 3H, CH3), 1.51 (m, 2H, SCH2CH2CH3 major), 1.59 (dt, J = 10.0 Hz / 5.4 Hz, 1H, 3'-Hb), 1.70 (h, J = 7.3 Hz, 0.4H, SCH2CH2CH3 minor), 2.14 (ddd, J = 9.6 Hz / 6.4 Hz / 3.3 Hz, 0.8H, 2'-H major), 2.24 (m, 0.2H, 2'-H minor), 2.52 (m, 1H, 5'''-Ha), 2.65 (m, 1H, 5'''-Hb), 2.87 (m, 1.6H, SCH2CH2CH3 major), 3.08 (m, 0.4H, SCH2CH2CH3 minor), 3.19 (dd, J=7.6 Hz / 4.2 Hz, 0.8H, 1'-H major), 3.39-3.51 (m, 4H, OCH2CH2OH), 3.75 (m, 0.2H, 1'-H minor), 4.00 (m, 1H, 4'''-H), 4.56 (t, J=5.2 Hz, 1H, OH), 4.64 (m, 0.2H, 3a'''-H minor), 4.67 (dt, J=7.0 Hz / 3.3 Hz, 0.8H, 3a'''-H major), 5.01 (m, 1H, 6'''-H), 5.16 (m, 0.2H, 6a'''-H minor), 5.20 (dt, J=7.3 Hz / 4.8 Hz, 0.8H, 6a'''-H major), 6.97 (d, J=7.1 Hz, 0.2H, 6''-H minor), 7.03 (dd, J=8.3 Hz / 1.9 Hz, 0.8H, 6''-H major), 7.18 (d, J=10.0 Hz, 0.2H, 2''-H minor), 7.24 (dd, J=10.4 Hz / 1.9 Hz, 0.8H, 2''-H major), 7.59 (t, J=7.9 Hz, 1H, 5''-H), 9.01 (d, J=4.7 Hz, 0.2H, NH minor), 9.41 (dd, J=3.9 Hz / 1.2 Hz, 0.8H, NH major). 13 C NMR (DMSO-d6) δ 13.0, 15.3, 22.3, 24.3, 24.8, 26.9, 32.4, 34.5, 35.4, 60.0, 61.4, 70.7, 81.9, 83.7, 104.5, 112.5, 114.1, 123.2, 123.9, 132.9, 144.3, 149.1, 153.9, 157.3, 159.3, 169.5.

[0079] Intermediate (4) was obtained by mixing (3) (0.62 g, 1.0 mmol), di-tert-butyl dicarbonate (1 g, 4.6 mmol) and 4-(dimethylamino)pyridine (30 mg, catalytic) in tetrahydrofuran (10 mL) and reacting the mixture overnight at room temperature. After evaporating the solvent, the residue was purified by silica gel column chromatography. Yield: 56% Melting point: 156~158℃. 1H NMR (DMSO-d6) δ0.99 (td, J=7.3 Hz / 2.6 Hz, 3H, SCH2CH2CH3), 1.28 (s, 3H, CH3), 1.35 (m, 1H, 3’-Ha), 1.39 (s, 9H, C(CH3)3), 1.40 (s, 9H, C(CH3)3), 1.50 (s, 3H, CH3), 1.55 (qd, J=7.2 Hz / 2.2 Hz, 1H, 3’-Hb), 1.70 (m, 2H, SCH2CH2CH3), 2.26 (m, 1H, 2’-H), 2.61 (m, 1H, 5’’’-Ha), 2.73 (m, 1H, 5’’’-Hb), 3.05 (m, 2H, SCH2CH2CH3), 3.27 (m, 1H, 1’-H), 3.62 (m, 2H, OCH2CH2OC(CH3)3), 4.04 (m, 3H, OCH2CH2OC(CH3)3 / 4’’’-H), 4.71 (dd, J=7.2 Hz / 3.0 Hz, 1H, 3a’’’-H), 5.15 (m, 1H, 6’’’-H), 5.27 (m, 1H, 6a’’’-H), 7.02 (dd, J=8.3 Hz / 1.9 Hz, 1H, 6’’-H), 7.24 (dt, J=10.4 Hz / 1.8 Hz, 1H, 2’’-H), 7.59 (t, J=7.9 Hz, 1H, 5’’-H). 13 C NMR (DMSO-d6) δ13.3, 18.1, 22.1, 24.7, 26.0, 26.8, 27.3, 27.4, 32.6, 35.1, 39.0, 61.8, 65.5, 66.7, 81.4, 82.0, 82.1, 82.8, 83.6, 104.9, 112.5, 114.7, 124.3, 127.8, 132.9, 143.4, 150.6, 152.3, 152.9, 154.3, 157.2, 159.1, 169.1.

[0080] Precursor (1): (3-((3aS,4R,6S,6aR)-6-(2-((tert-butoxycarbonyl)oxy)ethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)((1R,2S)-2-(3-fluoro-4-(trimethylstannyl)phenyl)cyclopropyl)carbamate (5) was prepared by mixing (4) (0.41 g, 0.5 mmol), hexamethyldistannane (0.49 g, 1.5 mmol) with tetrakis(triphenylphosphine)palladium(0) (10 mg, catalytic) in dry toluene (5 mL), placing the mixture in a sealed vessel, and heating it at 100 °C overnight under nitrogen. After cooling, ethyl acetate (50 mL) was added and the insoluble material was filtered off. The filtrate was evaporated to dryness and the resulting residue was purified by silica gel column chromatography. Yield: 65% Melting point: 60~62℃. 11H NMR (DMSO-d6) δ0.30 (s, 9H, Sn(CH3)3), 0.96 (td, J=7.3 Hz / 2.9 Hz, 3H, SCH2CH2CH3), 1.28 (s, 3H, CH3), 1.32 (m, 1H, 3’-Ha), 1.39 (s, 9H, C(CH3)3), 1.40 (s, 9H, C(CH3)3), 1.50 (m, 4H, CH3 / 3’-Hb), 1.67 (m, 2H, SCH2CH2CH3), 2.23 (m, 1H, 2’-H), 2.58 (m, 1H, 5’’’-Ha), 2.72 (m, 1H, 5’’’-Hb), 3.03 (m, 2H, SCH2CH2CH3), 3.24 (m, 1H, 1’-H), 3.61 (m, 2H, OCH2CH2OC(CH3)3), 4.03 (m, 3H, OCH2CH2OC(CH3)3 / 4’’’-H), 4.71 (d, J=7.1 Hz, 1H, 3a’’’-H), 5.15 (t, J=9.9 Hz, 1H, 6’’’-H), 5.27 (dt, J=7.9 Hz / 4.4 Hz, 1H, 6a’’’-H), 6.95 (m, 1H, 2’’-H), 7.02 (d, J=7.4 Hz, 1H, 6’’-H), 7.59 (m, 1H, 5’’-H). 13 13C NMR (DMSO-d6) δ -8.9, 13.3, 17.9, 22.1, 24.7, 26.2, 26.8, 27.3, 27.4, 32.6, 35.1, 39.0, 61.8, 65.5, 66.7, 81.4, 82.0, 82.1, 82.7, 83.6, 112.1, 112.5, 122.7, 123.6, 127.9, 136.4, 144.2, 150.6, 152.4, 152.9, 154.4, 166.1, 167.9, 169.1.

[0081] ii) Synthesis of yet another labeling precursor shown in Figure 2 Other precursors can be synthesized from (5) using hydroxy(tosyloxy)iodobenzene (step (vi)) to give the corresponding iodonium tosylate (6), or using iodine (step (vii)) to give (7), followed by the addition of Meldrum's acid (step (viii)) to give the iodonium ylide (8).

[0082] The labeled precursor (6) is obtained by adding hydroxy(tosyloxy)iodobenzene (0.13 g, 0.33 mmol) to a solution of (5) (0.27 g, 0.3 mmol) in dichloromethane (5 mL) at 0 °C. The resulting mixture is reacted at room temperature for 1 h. After evaporation of the solvent, the residue is purified by silica gel column chromatography. Yield: 72%. Melting point: 92~95℃. 1 H NMR (DMSO-d6) δ0.96 (t, J=7.0 Hz, 3H, SCH2CH2CH3), 1.27 (s, 3H, CH3), 1.37 (s, 9H, C(CH3)3), 1.39 (s, 9H, C(CH3)3), 1.43 (m, 1H, 3'-Ha), 1.50 (s, 3H, CH3), 1.63 (m, 3H, SCH2CH2CH3 / 3'-Hb), 2.29 (s, 3H, CH 3 tos ), 2.32 (m, 1H, 2'-H), 2.57 (m, 1H, 5'''-Ha), 2.72 (m, 1H, 5'''-Hb), 2.83-3.07 (m, 2H, SCH2CH2CH3), 3.30 (m, 1H, 1'-H), 3.62 (m, 2H, OCH2CH2OC(CH3)3), 4.04 (m, 3H, OCH2CH2OC(CH3)3 / 4'''-H), 4.70 (dd, J=7.2 Hz / 2.9 Hz, 1H, 3a'''-H), 5.14 (m, 1H, 6'''-H), 5.25 (dd, J=7.0 Hz / 4.6 Hz, 1H, 6a'''-H), 7.11 (d, J=7.8 Hz, 2H, 3H tos / 5-H tos), 7.20 (dd, J=8.4 Hz / 1.7 Hz, 1H, 6''-H), 7.41 (dd, J=10.0 Hz / 1.6 Hz, 1H, 2''-H), 7.47 (d, J=8.1 Hz, 2H, 2-H tos / 6-H tos ), 7.54 (t, J=7.8 Hz, 2H, 3''''-H / 5''''-H), 7.68 (t, J=7.4 Hz, 1H, 4''''-H), 8.21 (d, J=7.6 Hz, 2H, 2''''-H / 6''''-H), 8.29 (dd, J=8.2 Hz / 6.6 Hz, 1H, 5''-H). 13 C NMR (DMSO-d6) δ13.2, 19.0, 20.8, 22.1, 24.7, 26.5, 26.8, 27.3, 27.4, 32.5, 35.2, 39.9, 61.8, 65.5, 66.7, 81.4, 82.0, 82.9, 83.6, 100.3, 112.5, 114.5, 117.0, 125.5, 127.8, 128.0, 131.9, 132.2, 135.0, 136.5, 137.5, 145.9, 150.6, 152.2, 152.9, 154.1, 158.3, 160.3, 169.0.

[0083] The labeled precursor (3-((3aS,4R,6S,6aR)-6-(2-((tert-butoxycarbonyl)oxy)ethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)((1R,2S)-2-(3-fluoro-4-iodophenyl)cyclopropyl)carbamate tert-butyl ester (7) was obtained by adding iodine (0.15 g, 0.6 mmol) to a solution of (5) (0.27 g, 0.3 mmol) in dichloromethane (5 mL). The resulting mixture was reacted at room temperature for 1 h. After evaporation of the solvent, the residue was purified by silica gel column chromatography. Yield: 61%. Melting point: 151-153°C. 1 1H NMR (DMSO-d6) δ 0.98 (t, J = 7.3 Hz, 3H, SCH2CH2CH3), 1.28 (s, 3H, CH3), 1.34 (m, 1H, 3’-Ha), 1.39 (s, 9H, C(CH3)3), 1.40 (s, 9H, C(CH3)3), 1.50 (s, 3H, CH3), 1.53 (q, J = 6.9 Hz, 1H, 3’-Hb), 1.70 (h, J = 7.3 Hz, 2H, SCH2CH2CH3), 2.24 (m, 1H, 2’-H), 2.59 (m, 1H, 5’’’-Ha), 2.72 (m, 1H, 5’’’-Hb), 3.05 (m, 2H, SCH2CH2CH3), 3.26 (m, 1H, 1’-H), 3.56 - 3.68 (m, 2H, OCH2CH2OC(CH3)3), 4.03 (m, 3H, OCH2CH2OC(CH3)3 / 4’’’-H), 4.70 (dd, J = 7.2 Hz / 3.0 Hz, 1H, 3a’’’-H), 5.15 (m, 1H, 6’’’-H), 5.26 (m, 1H, 6a’’’-H), 6.87 (dd, J = 8.2 Hz / 1.8 Hz, 1H, 6’’-H), 7.13 (dt, J = 9.7 Hz / 1.8 Hz, 1H, 2’’-H), 7.71 (dd, J = 7.9 Hz / 7.1 Hz, 1H, 5’’-H). 13 13C NMR (DMSO-d6) δ 13.3, 18.1, 22.1, 24.7, 26.1, 26.8, 27.3, 27.4, 31.0, 32.6, 35.1, 39.1, 61.9, 65.5, 66.7, 78.3, 78.5, 81.4, 81.9, 82.0, 82.7, 83.6, 112.5, 113.7, 113.9, 124.7, 127.9, 138.6, 144.0, 150.6, 152.3, 152.9, 154.3, 160.2, 162.1, 169.1.

[0084] iii) Labeling precursors (6) and (8) 18 Conversion to F-triacyls. The iodonium groups of both labeling precursors (6) and (8) were prepared by processes described in the literature. 18 Converted to F-triafluosyl: Reference for precursor (6): Copper-Mediated Radiofluorination of Arylstannanes with [18F]KF; Makaravage, Katarina J.; Brooks, Allen F.; Mossine, Andrew V.; Sanford, Melanie S.; Scott, Peter JH (Organic Letters (2016), 18(20), 5440-5443) Reference for precursor (8): Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics; Rotstein, Benjamin H.; Stephenson, Nickeisha A.; Vasdev, Neil; Liang, Steven H. (Nature Communications (2014), 5, 4365) Example 2

[0085] In vitro 18 F-triafluosyl and 18 Comparison of F-FDG uptake assays 18 To evaluate the selective uptake of F-triafluosyl into bacteria and its utility for the specific diagnosis of bacterial infection, we 18 F-triafluosyl and 18 An in vitro assay was performed to compare bacterial uptake of F-FDG. For this purpose, Staphylococcus epidermidis 18 F-FDG or 18 After incubation with F-triafluosyl, the relative radioactivity bound to bacterial cells was determined as follows. S. epidermidis was grown overnight in Trypticase soy broth (TSB) at 37°C with shaking at 250 rpm. The overnight culture was analyzed at OD 600 0.1 and incubated until the cells reached mid-exponential growth phase. 8 CFU were resuspended in 1 ml of cell culture medium RPMI 1640 (R7638) provided by Sigma-Aldrich. Bacteria and bacteria-free controls were prepared using 2MBq of PBS prepared as described in Example 1. 18 F-FDG or 2MBq 18 The cells were incubated with F-triafluosyl at 37°C for 1 hour. The bacteria were collected by centrifugation (600 x g, 5 min) and washed three times by successive centrifugations. After washing, the cells were transferred to a scintillation vial. The supernatant was also collected in a scintillation vial. The bacteria and supernatant were counted in a gamma counter (2470 Wizard 2 (trademark) (Perkin Elmer). Results were obtained as counts per minute and were normalized to a control (no bacteria) and by calculating the percentage of radioactivity in the cell-containing scintillation vial compared to the total counts (cells and supernatant combined). After incubation with bacteria, we bind to bacterial cells. 18 The relative radioactivity of F-triafluosyl is 18 The radioactivity was found to be 1.5 to 2 times higher than that of F-FDG. Example 3

[0086] In vitro prognosis and / or diagnosis of bacterial infection from a blood sample obtained from a host mammal (human) 18 Use of F-triafluosyl. Because it is well known in the art that triafluosyl (also known as ticagrelor) reversibly binds to platelet P2Y12 receptors, leading to platelet accumulation at sites of bacterial infection (as described in Hamzeh-Cognasse H, Damien P, Chabert A, Pozzetto B, Cognasse F, Garraud O. Platelets and infections - complex interactions with bacteria. Front Immunol. 2015;6:82. Published 2015 Feb 26. doi:10.3389 / fimmu.2015.00082), we also compared the uptake of the radiotracer into human platelets in the presence or absence of bacteria. Preparation of human washed platelets: Blood samples were collected from healthy volunteers on acid citrate dextrose (ACD: 93 mM Na citrate, 7 mM citric acid, 14 mM dextrose, pH 6.0) containing 1 U / ml apyrase at a volume ratio of 1:6. Platelet-rich plasma (PRP) was obtained by centrifuging the blood at 800 × g for 5 seconds, followed by 100 × g for 5 minutes. PRP was diluted 3-fold with ACD containing 1 U / ml apyrase (potato-derived apyrase, Grade I (A6132 Sigma-Aldrich)) and centrifuged at 1000 × g to obtain a platelet pellet. The platelet pellet was diluted to 3 × 10 in Tyrode's buffer (137 mM NaCl, 12 mM NaHCO, 2 mM KCl, 0.34 mM NaHPO, 1 mM MgCl, 5.5 mM glucose, 5 mM Hepes, 0.35% bovine serum albumin from Sigma Aldrich A3294). 8 The solution was resuspended at a concentration of 100 ml, where HEPES refers to 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (H4034, Sigma-Aldrich). Bacteria, platelets, and a bacteria-free control were added at 2 MBq 18 F-FDG or 2MBq 18The cells were incubated with F-triafluosyl at 37°C for 1 hour. Bacteria and platelets were collected by centrifugation (1000 x g, 10 min) and washed three times by successive centrifugations (1000 x g, 10 min). The supernatant was collected in a scintillation vial. After washing, the cells were transferred to a scintillation vial. The cells and supernatant were counted in a gamma counter (2470 Wizard 2 (trademark) (Perkin Elmer). Results were obtained as counts per minute and were normalized to a control (no cells) and by calculating the percentage of radioactivity in the cell-containing scintillation vial compared to the total counts (cells and supernatant combined). The results are: 18 F-triafluosyl uptake into platelets was confirmed, 18 Furthermore, after incubation with platelet suspensions containing bacteria, we found that F-FDG bound to the cell mixture was not transported into these cells. 18 The relative radioactivity of F-triafluosyl is 18 The radioactivity was found to be approximately 10 times higher than that of F-FDG. Example 4

[0087] For the prognosis and / or diagnosis of bacterial infection of mammalian cells obtained from a human host 18 Selective use of F-triafluosyl S. epidermidis was grown overnight in trypticase soy broth (TSB) at 37°C with shaking at 250 rpm. The overnight culture was analyzed at OD 600 0.1 and incubated until the cells reached mid-exponential growth phase. 8 CFU were resuspended in 1 ml of RPMI 1640. 1 × 10 8 CFU were resuspended in 1 ml of RPMI 1640. THP1 (ATCC® TIB-202™) and HL60 (ATCC® CCL-240™) cell lines were grown in RPMI 1640 tissue culture medium supplemented with L-glutamine, 10% fetal bovine serum, and 1% penicillin / streptomycin at 37°C and 5% CO2. The HT29 cell line (ATCC® HTB-38) was grown in McCoy's 5A medium and 10% fetal bovine serum at 37°C and 5% CO2. Non-adherent cell line (HL60, THP1; 1×10 6 cells ml -1 ) were harvested, washed, and resuspended in 1 ml of tissue culture medium. Adherent HT29 cells were maintained in 6-well plates at 80% confluence. Bacteria, cell lines, and cell-free controls were analyzed using 2MBq 18 F-FDG or 2MBq 18 The cells were incubated with F-ticagrelor for 1 hour at 37°C. Bacteria and non-adherent cells were collected by centrifugation (600 x g, 5 minutes) and washed three times by successive centrifugations. The cell supernatant was collected in a scintillation vial. After washing, the cells were transferred to a scintillation vial. Adherent cells were washed three times with fresh medium (McCoy's 5A medium supplemented with 10% fetal bovine serum). The supernatant was collected in a scintillation vial. Adherent cells were detached by trypsinization and placed in a scintillation vial. The scintillation vials for cells and supernatant were counted in a gamma counter. Results were obtained as counts per minute. Results were normalized by calculating the percentage of radioactivity in the cell-containing scintillation vial compared to the control (without bacteria) and the total count (cells and supernatant combined). The results are: 18 Although we confirmed the uptake of F-triafluosyl into bacteria, we did not observe uptake in either mammalian leukocytes (THP1 and HL-60) or tumor (HT29) cells. In contrast, we did not observe uptake in three mammalian cell lines. 18 The uptake of F-FDG was observed. 18F-triafluosyl can be used for the specific in vitro detection of bacterial infections in human-derived samples. Example 5

[0088] In vivo prognostic and / or diagnostic protocols Test protocols have been established for the in vivo prognosis and / or diagnosis of bacterial infection in patients, and include the use of ribosomal RNA as a radioactive tracer. 18 Compatible with the use of F-triafluosyl. The following protocol was developed for PET-CT imaging, but one skilled in the art could easily extrapolate it to other imaging techniques, such as SPECT. The protocol is based on the same image acquisition for each patient. 3.7MBq after at least 6 hours of fasting 18 Inject F-triafluosyl / kg body weight (mean radioactivity / patient: 277 MBq, range: 202-394 MBq) through a peripheral venous catheter. The patient is placed in a quiet room and instructed not to move. 18 Approximately 1 hour (mean: 69 minutes, range: 54-100 minutes) after the injection of F-triafluosyl, a static whole-body examination is performed with a PET-CT scanner. Volumetric low-dose axial CT images are acquired. Next, raw radiometric images are recorded at each bed and reconstructed as overlapping coronal slices after scatter correction (convolution subtraction) and normalization correction based on the CT attenuation model. This protocol is applicable to patients with bacterial infections that can be deep-seated in all tissues of the patient's body, including muscle, epithelium, connective tissue, and nerves, while patients with cancer or sterile inflammation are less likely to be detected by this protocol.

Claims

1. 1. A pharmaceutical composition for use in the diagnosis of an in vivo bacterial infection in a host mammal, comprising: Formula (I): 【Chemistry 4】 [In the formula, R １ is a C optionally substituted by one or more halogen atoms ３－５ alkyl; R ２ is a phenyl group substituted by one or more halogen atoms; R ３ and R ４ are each hydroxyl; R is XOH, where X is CH ２ , OCH ２ CH ２ or a bond], or a pharmaceutically acceptable salt or solvate thereof, or a solvate of said salt, ２ or a bond, R １ is not propyl; X is CH ２ and R １ But CH ２ CH ２ CF ３ butyl or pentyl, R ２ The phenyl group of must be substituted with fluorine; ２ CH ２ and R １ is propyl, R ２ the phenyl group must be substituted with fluorine; and Pharmaceutically acceptable excipients Including, One halogen atom of the derivative is a detectable marker １８ A pharmaceutical composition characterized in that it is F.

2. R ２ The pharmaceutical composition of claim 1 , wherein is phenyl substituted with a fluorine atom.

3. R is OH or OCH ２ CH ２ 3. The pharmaceutical composition according to claim 1 or 2, wherein the compound is OH.

4. 4. The pharmaceutical composition of claim 3, wherein R is OH.

5. 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the derivative is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol, also known as Triafluocyl.

6. 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the derivative is (1S,2R,3S,4R)-4-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-1,2,3-cyclopentanetriol, also known as Fluometacyl.

7. 7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the bacterial infection is caused by one or more bacteria selected from Staphylococcus aureus (S. aureus), Staphylococcus epidermidis, E. faecalis, E. faecium, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), glycopeptide-intermediate Staphylococcus aureus (GISA), coagulase-negative staphylococci (CoNS), vancomycin-resistant enterococci (VRE), beta-hemolytic Streptococcus agalactiae (Group B Streptococcus, GBS) or other streptococci.

8. 7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the bacterial infection is caused by one or more bacteria selected from Acinetobacter baumannii, Pseudomonas aeruginosa, carbapenem-resistant Pseudomonas aeruginosa, Enterobacteriaceae, and third-generation cephalosporin-resistant Enterobacteriaceae (Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp., and Morganella spp.).

9. 10. A method for imaging a bacterial infection in a host mammal, comprising tracking a triazolo[4,5-d]pyrimidine derivative as defined in any one of claims 1 to 6 by an imaging technique to display the bacterial infection.

10. The method of imaging a bacterial infection according to claim 9, wherein the imaging technique is single photon emission computed tomography (SPECT), computed tomography (CT), single photon emission computed tomography (SPECT) with computed tomography (CT), positron emission tomography (PET), positron emission tomography with computed tomography (CT), or positron emission tomography with magnetic resonance.

11. 11. The method of imaging a bacterial infection in a host mammal according to claim 9 or 10, wherein the bacterial infection is caused by one or more bacteria selected from Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), glycopeptide-intermediate Staphylococcus aureus (GISA), coagulase-negative Staphylococci (CoNS), vancomycin-resistant enterococci (VRE), beta-hemolytic streptococci (group B streptococci, GBS) or other streptococci.

12. 11. The method for imaging a bacterial infection in a host mammal according to claim 9 or 10, wherein the bacterial infection is caused by one or more bacteria selected from Acinetobacter baumannii, Pseudomonas aeruginosa, carbapenem-resistant Pseudomonas aeruginosa, Enterobacteriaceae, and third-generation cephalosporin-resistant Enterobacteriaceae (Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp., and Morganella spp.).

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