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Probes for 18F Positron Emission Tomography Imaging

20180340001 ยท 2018-11-29

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention contemplates a method for synthesizing [.sup.18F] fluoride complexes suitable for performing radio-labeling reactions to generate [.sup.18F] fluorinated species for use as imaging agents. The present invention further contemplates kits for making [.sup.18F] fluoride complexes suitable for performing radio-labeling reactions to generate [.sup.18F] fluorinated species. The present invention further contemplates a method of using [.sup.18F] fluoride prosthetic group for targeted tissue and disease imaging.

    Claims

    1. A compound with the structure: ##STR00022##

    2. The compound of claim 1, wherein at least one F is .sup.18F

    3. A compound with the structure: ##STR00023##

    4. The compound of claim 3, wherein at least one F is .sup.18F

    5. A method for the radiofluorination of a phosphorus(V) fluoride compound comprising: (a) providing: (i) a phosphorus(V) fluoride compound, and (ii) an [.sup.18F] source, (iii) an isotopic exchange promoter, and (b) isotopically exchanging the fluoride in said phosphorus(V) fluoride compound with the [.sup.18F] of said [.sup.18F] source with said isotopic exchange promoter to create an [.sup.18F]phosphorus(V) fluoride compound.

    6. The method of claim 5, wherein said phosphorus(V) fluoride compound comprises a zwitterionic compound containing a formally anionic phosphorus(V) fluoride moiety bound to a formally cationic group

    7. The method of claim 6, wherein said cationic group is selected from the group consisting of an ammonium, an iminium, an anilinium, a phopshoniun, a sulfonium, an arsonium, a stibonium, a selenonium, and a telluronium.

    8. The method of claim 6, wherein said cationic group comprises organic groups amenable to facile conjugation with biomolecules.

    9. The method of claim 8, wherein said organic groups amenable to facile conjugation with biomolecules are terminated by a functional group selected from the consisting of an alkyne, an azide, a thiol, a caroxilic acid, an N-succinimde ester, a maleimide, a sulfonate, a triflate, and an amine.

    10. The method of claim 5, wherein said phosphorus(V) fluoride compound is a N-heterocyclic carbene phosphorus(V) fluoride derivative.

    11. The method of claim 5, wherein said isotopic exchange promoter is SnCl.sub.4.

    12. The method of claim 11, wherein said method further comprises step (c) quenching with water.

    13. The method of claim 5, wherein said [.sup.18F] source is [.sup.18F]-tetra-n-butylammonium fluoride.

    14. The method of claim 10, wherein said N-heterocyclic carbene phosphorus(V) fluoride derivative is ##STR00024##

    15. The method of claim 10, wherein said N-heterocyclic carbene phosphorus(V) fluoride derivative is ##STR00025##

    16. A method for preparing .sup.18F-phosphorous-based radiotracers comprising: (a) providing; (i) a phosphorus(V) fluoride compound; (ii) an [.sup.18F] source; (iii) an isotopic exchange promoter; (iv) a biomolecule; (b) isotopically exchanging the fluoride in said phosphorus(V) fluoride compound with the [.sup.18F] of said [.sup.18F] source with said isotopic exchange promoter to create an [.sup.18F]phosphorus(V) fluoride compound; (c) quenching the exchange reaction with water, (d) isolating said [.sup.18F] phosphorus(V) fluoride compound, and (e) attaching said [.sup.18F] phosphorus(V) fluoride compound to said biomolecule so as to produce a .sup.18F-phosphorous-based radiotracer.

    17. The method of claim 16, wherein said phosphorus(V) fluoride compound is a N-heterocyclic carbene phosphorus(V) fluoride derivative.

    18. The method of claim 16, wherein said isotopic exchange promoter is SnCl.sub.4.

    19. The method of claim 16, wherein said source of [.sup.18F] is [.sup.18F]-tetra-n-butylammonium fluoride.

    20. The method of claim 16, wherein said N-heterocyclic carbene phosphorus(V) fluoride derivative is ##STR00026##

    21. The method of claim 16, wherein said N-heterocyclic carbene phosphorus(V) fluoride derivative is ##STR00027##

    22. The method of claim 16, wherein said .sup.18F-phosphorous-based radiotracer is for PET imaging applications

    23. A method for synthesizing a compound with the structure ##STR00028## comprising: a) providing: i) dichlorophenylphosphine; ii) potassium fluoride; and iii) bromine; b) adding bromine to a mixture of potassium fluoride and dichlorophenylphosphine to produce a first reaction mixture; c) stirring said first reaction mixture under such conditions that a reaction occurs; d) evaporating volatile compounds produced by said reaction to produce a residue; e) dissolving said residue in acetonitrile to produce a solution; f) filtering said solution; g) evaporating volatile compounds from said solution to produce a solid residue. h) washing said solid residue with diethyl ether, and i) drying said product with the structure ##STR00029##

    24. A method for synthesizing a compound with the structure ##STR00030## comprising: a) providing: i) a compound with the structure ##STR00031## ii) n-Butyllithium; and iii) dimethylimidazolium iodide; b) adding said n-Butyllithium a mixture of ##STR00032## and dimethylimidazolium iodide to produce a first reaction mixture; c) stirring said first reaction mixture under such conditions that a reaction occurs; d) evaporating volatile compounds produced by said reaction to produce a solid product; e) washing said solid product with water, f) washing said solid with ethanol, and g) drying said product with the structure ##STR00033##

    25. The method of claim 24, wherein said adding n-Butyllithium to said mixture is under 70 C.

    26. The method of claim 24, wherein said conditions comprise heating said first reaction mixture to room temperature, then to 65 C.

    27. A method of imaging the body of a subject comprising: a) providing: i) a subject comprising a tissue, and ii) a [.sup.18F]N-heterocyclic carbene phosphorus(V) fluoride derivative, b) administering said [.sup.18F]N-heterocyclic carbene phosphorus(V) fluoride derivative to said subject, and c) imaging said tissue.

    28. The method of claim 27, wherein said tissues comprises an organ.

    29. The method of claim 27, wherein said [.sup.18F]N-heterocyclic carbene phosphorus(V) fluoride derivative is in a form suitable for mammalian administration.

    30. The method of claim 27, wherein said imaging comprises generating a Positron Emission Tomography image.

    31. The method of claim 27, wherein said imaging is preferably carried out where the part of said tissue is diseased.

    32. The method of claim 27, wherein said [.sup.18F]N-heterocyclic carbene phosphorus(V) fluoride derivative is ##STR00034##

    33. The method of claim 27, wherein said [.sup.18F]N-heterocyclic carbene phosphorus(V) fluoride derivative is ##STR00035##

    34. The method of claim 27, wherein said [.sup.18F]N-heterocyclic carbene phosphorus(V) fluoride derivative is attached as a prosthetic group to a biomolecule.

    35. A kit, comprising: a) a first container with a N-heterocyclic carbene phosphorus(V) fluoride derivative, b) a second container with SnCl.sub.4, c) a third container for a [.sup.18F] source, d) a solid-phase extraction cartridge, and e) instructions for use of said kit.

    36. The kit of claim 35, wherein said N-heterocyclic carbene phosphorus(V) fluoride derivative is ##STR00036##

    37. The kit of claim 35, wherein said N-heterocyclic carbene phosphorus(V) fluoride derivative is ##STR00037##

    38. The kit of claim 35, wherein said kit further includes a fourth container with water.

    39. The kit of claim 35, wherein said kit further includes a fifth container with anhydrous solvent.

    40. The kit of claim 35, wherein said solid-phase extraction cartridge has a silica-based bonded phase with strong hydrophobicity and trifunctional bonding chemistry.

    41. The kit of claim 35, wherein said instructions for use comprises: a) obtaining a [.sup.18F] source, b) mixing the contents of said a first container with the contents of said second container with an anhydrous solvent to create a first exchange reaction mixture, c) combining said [.sup.18F] source with said first exchange reaction mixture, d) incubating said first exchange reaction mixture for at least 10 minutes, e) adding water to said reaction mixture to quench said reaction mixture, f) passing the quenched reaction mixture through said solid-phase extraction cartridge, g) passing water through said solid-phase extraction cartridge, and h) eluting the resulting [.sup.18F]N-heterocyclic carbene phosphorus(V) fluoride derivative from said solid-phase extraction cartridge with anhydrous solvent.

    42. The kit of claim 41, wherein said anhydrous solvent is anhydrous acetonitrile.

    43. The kit of claim 41, wherein said [.sup.18F] source comprises [.sup.18F]-tetra-n-butylammonium fluoride.

    44. The kit of claim 41, wherein said incubating occurs at a temperature between room temperature and 100 C.

    Description

    DESCRIPTION OF THE FIGURES

    [0043] The accompanying figures, which are incorporated into and form a part of the specification, illustrate several embodiments of the present invention and, together with the description, serve to explain the principles of the invention. The figures are only for the purpose of illustrating a preferred embodiment of the invention and are not to be construed as limiting the invention.

    [0044] FIG. 1 shows a wide range of known peptide based radiotracers.

    [0045] FIG. 2 shows N-heterocyclic carbene (NHC) phosphorus(V) fluoride derivatives as contemplated by one embodiment of the present invention.

    [0046] FIG. 3 shows an exemplary synthesis of target compound 2.

    [0047] FIG. 4 shows an illustrative ORTEP diagram of 2. Thermal ellipsoids are shown at the 50% probability level. Hydrogen atoms are omitted for clarity. Selected bond distances () and angles (): P(1)-C(6)=1.839(2); P(1)-F(1)=1.634(1); P(1)-F(2)=1.642(1); P(1)-F(3)=1.631(1); P(1)-F(4)=1.645(1); P(1)-C1)=1.898(2); C(I)P(1)-(C6)=178.96(6); F(2-P(1)-F(4)=175.75(4); C(6)-P(1)-F(1)=91.76(6).

    [0048] FIG. 5 shows illustrative ORTEP diagrams of the asymmetric unit (top) and of the packing (bottom) of KPF.sub.5Ph (1). Thermal ellipsoids are shown at the 50% probability level. Hydrogen atoms and K, CH.sub.3CN labels are omitted for clarity. Blue: nitrogen atoms, green: fluorine atoms, purple: potassium atoms, orange: phosphorus atoms, grey: carbon atoms.

    [0049] FIG. 8 shows exemplary data of kinetic plots for the hydrolysis of 2.

    [0050] FIG. 6 shows exemplary data of a .sup.18F{.sup.1H} NMR analysis of an aliquot of the crude reaction mixture for the synthesis of 2 after addition of n-BuLi. The aliquot of the crude mixture is heated at 66 C. and analyzed over time by .sup.19F {.sup.1H} NMR.

    [0051] FIG. 7 shows a typical ratio of NHCPF.sub.4Ph cis and trans (2) isomers during time at 66 C. in THF Ratios are calculated by .sup.19F NMR integration using BF.sub.3.EtO as internal standard.

    [0052] FIG. 9 shows an exemplary .sup.19F NMR spectrum of 1 in D.sub.2O-CD.sub.3CN (8/2 vol) phosphate buffer solution at t=0 and t=5 days.

    [0053] FIG. 10A shows an exemplary UV-HPLC chromatogram of the acetonitrile (MeCN) portion obtained after radiolabeling of 1 at 100 C.

    [0054] FIG. 10B shows an exemplary Radio-HPLC chromatogran of the acetonitrile (MeCN) portion obtained after radiolabeling of 1 at 100 C.

    [0055] FIGS. 11A&B shows an exemplary decay-corrected whole-body microPET-CT images of nude mice from a static scan at 3 h after injection of [.sup.18F]-1. FIG. 11A shows the coronal image, FIG. 11B shows sagittal image.

    [0056] FIG. 12A shows an exemplary UV-HPLC chromatogram of the acetonitrile (MeCN) portion obtained after radiolabeling of 1 at 100 C.

    [0057] FIG. 12B shows an exemplary Radio-HPLC chromatogram of the acetonitrile (MeCN) portion obtained after radiolabeling of 1 at 100 C.

    [0058] FIG. 13 shows an exemplary .sup.1H NMR spectra of [K][PF.sub.5Ph].

    [0059] FIG. 14 shows an exemplary .sup.13C NMR spectra of [K][PF.sub.5Ph].

    [0060] FIG. 15 shows an exemplary .sup.31P NMR spectra of[K][PF.sub.5Ph].

    [0061] FIG. 16 shows an exemplary .sup.19F NMR spectra of [K][PF.sub.5Ph].

    [0062] FIG. 17 shows an exemplary .sup.1H NMR spectra of (NHC)PF.sub.4Ph 2.

    [0063] FIG. 18 shows an exemplary .sup.13C NMR spectra of (NHC)PF.sub.4Ph 2.

    [0064] FIG. 19 shows an exemplary .sup.31P NMR spectra of (NHC)PF.sub.4Ph 2.

    [0065] FIG. 20 shows an exemplary .sup.19F NMR spectra of (NHC)PF.sub.4Ph 2.

    [0066] FIG. 21 shows an exemplary HRMS spectra of [K][PF.sub.5Ph].

    [0067] FIG. 22 shows an exemplary HRMS spectra of (NHC)PF.sub.4Ph 2.

    DETAILED DESCRIPTION OF THE INVENTION

    [0068] The present invention contemplates a method for synthesizing [.sup.18F] fluoride complexes suitable for performing radio-labeling reactions to generate [.sup.18F] fluorinated species for use as imaging agents. The present invention further contemplates kits for making [.sup.18F] fluoride complexes suitable for performing radio-labeling reactions to generate [.sup.18F] fluorinated species. The present invention further contemplates a method of using a [.sup.18F] fluoride prosthetic group for targeted tissue and disease imaging.

    [0069] It will be readily understood that the components of the embodiments as generally described herein and illustrated in the appended figures could be arranged and designed in a wide variety of different configurations. Thus, the following more detailed description of various embodiments, as represented in the figures, is not intended to limit the scope of the present disclosure, but is merely representative of various embodiments. While the various aspects of the embodiments are presented in drawings, the drawings are not necessarily drawn to scale unless specifically indicated.

    [0070] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by this detailed description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

    [0071] Reference throughout this specification to features, advantages, or similar language does not imply that all of the features and advantages that may be realized with the present invention should be or are in any single embodiment of the invention. Rather, language referring to the features and advantages is understood to mean that a specific feature, advantage, or characteristic described in connection with an embodiment is included in at least one embodiment of the present invention. Thus, discussions of the features and advantages, and similar language, throughout the specification may, but do not necessarily, refer to the same embodiment.

    [0072] Furthermore, the described features, advantages and characteristics of the invention may be combined in any suitable manner in one or more embodiments. One skilled in the relevant art will recognize, in light of the description herein, that the invention can be practiced without one or more of the specific features or advantages of a particular embodiment. In other instances, additional features and advantages may be recognized in certain embodiments that may not be present in all embodiments of the invention.

    [0073] Reference throughout this specification to one embodiment, an embodiment, or similar language means that a particular feature, structure, or characteristic described in connection with the indicated embodiment is included in at least one embodiment of the present invention. Thus, the phrases in one embodiment, in an embodiment, and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

    [0074] In one embodiment, the invention contemplates a method for the radiofluorination of N-heterocyclic carbene (NHC) phosphorus(V) fluoride adducts. In one embodiment, the IMe-PF5 derivative (IMe=1,3-dimethylimidazol-2-ylidene) undergoes Lewis acid promoted .sup.18F-.sup.19F isotopic exchange. In one embodiment, the resulting radiofluorinated probe is remarkably resistant to hydrolysis. This is supported by both in vitro and in vivo studies described herein. In the in vitro studies, the release of free fluoride after incubating this probe in aqueous solution (pH 7.5, 80% water/20% acetonitrile) for five days was not observed. In the in vivo studies, free [.sup.18F]-fluoride signal was not observed in a murine model during the full range of the imaging experiment which lasted 3 hours post-injection. Past that point the natural radioactive decay of the fluorine-18 radionuclide led to low signal intensity such that the probe could no longer be studied.

    [0075] Positron Emission Tomography (PET) is a rapidly growing imaging technique that relies on the use molecular radiotracers containing a positron emitting isotope. To date, a great deal of attention has been devoted to the use of fluorine-18 [.sup.18F], a radionuclide that can be easily generated from [.sup.18O]-water and whose nuclear decay characteristics are ideally suited for applications in PET imaging. One difficulty faced in the synthesis of .sup.18F-containing molecular radiotracers is the short half-life of the isotope (110 min). It follows that the best methods to access .sup.18F-containing molecular radiotracers should be fast and preferably carried out in the late stages of the synthesis of the radiopharmaceutical probe. An attractive approach that provides a possible solution to these challenges is based on molecules containing a main group element as a fluoride binding site. In one embodiment, the invention contemplates the preparation of an .sup.18F-phosphorous-based radiotracer for PET imaging applications. In one embodiment, this new tracer is extremely stable in vivo and has a potential to be used to conjugate with drugs, peptides, proteins, or any diagnostic biomolecules which can be produced as commercial products in pharmaceutical or radiopharmaceutical industries.

    [0076] McBride and colleagues have also developed many compositions and methods of synthesis and use of .sup.18F labeled molecules of use, for example, in PET imaging techniques [8-15]. However, in terms of .sup.18F compounds, undoubtedly, boron-based prosthetic group pioneered by Perrin et al.[16-20] are the most developed. The most versatile example is the alkyne linked zwitterionic ammonium trifluoroborate which can be incorporated in a wide range of peptide based radiotracers. In parallel to these advances, the current invention introduces zwitterionic phosphonium trifluoroborates and carbene-BF.sub.3 adducts which can be conjugated to biomolecule. Following up on these results, there was an attraction to the fluorophilic properties of phosphorus (V) compounds. Indeed, based on computed gas phase fluoride ion affinity data (346 kJ mol1 for BF.sub.3 and 380 kJ mol1 for PFS), which show that P(V) species may be more Lewis acidic than boron (III) derivatives, it was determined that phosphorus analogs of the BF.sub.3-carbene might be ideally suited for application in PET. To explore this idea and expand on the limited chemistry of radiofluorinated phosphorus compounds, there was an investigation of the radiofluorination of the N-heterocyclic carbene (NHC) phosphorus(V) fluoride derivatives. In some embodiments, this invention contemplates the synthesis and production of compounds not previously used as radiotracers before. In one embodiment, the current invention contemplates a method of administering a .sup.18FPFS-carbene into mice under conditions that demonstrate in vivo stability. In the in vitro studies, the release of free fluoride after incubating this probe in aqueous solution (pH 7.5, 80% water/20% acetonitrile) for five days was not observed. In the in vivo studies, free [18F]-fluoride signal was not observed in a murine model during the full range of the imaging experiment which lasted 3 hours post-injection. Past that point the natural radioactive decay of the fluorine-18 radionuclide led to low signal intensity such that the probe could no longer be studied.

    INTRODUCTION

    [0077] A growing area of radiochemistry is concerned with the discovery of radiolabeled prosthetic groups which, once appended to tissue- or disease-specific biomolecules, provide a modular access to novel Positron Emission Tomography (PET) [21] imaging agents [22-24]. To date, most imaging agents (prosthetic groups) contain a group 13 element (comprising boron (B), aluminum (Al), gallium (Ga), indium (In), thallium (TI)) [22, 25-32] or group 14 element (carbon (C), silicon (Si), germanium (Ge), tin (Sn), lead (Pb), and flerovium (Fl)) which serves as binding site for the fluoride anion [23, 33, 34]. Undoubtedly, boron-based prosthetic groups pioneered by Perrin are the most developed [16-20]. The most versatile example is the alkyne linked zwitterionic ammonium trifluoroborate (I) which can be incorporated in a wide range of peptide based radiotracers (FIG. 1) [35-39]. In parallel to these advances, zwitterionic phosphonium trifluoroborates (II) and carbene-BF.sub.3 adducts (III) were introduced which, like I, can be conjugated to biomolecule [40-42]. Following up on these results, there was attention given to the fluorophilic properties of phosphorus (V) compounds [43-45]. Indeed, based on computed gas phase fluoride ion affinity data (346 kJ mol.sup.1 for BF.sub.3 and 380 kJ mol.sup.1 for PF.sub.5), which show that P(V) species may be more Lewis acidic than boron (EII) derivatives, phosphorus analogs of III appeared suited for application in PET.

    [0078] To explore this idea and expand on the limited chemistry of radiofluorinated phosphorus compounds [46, 47], there was an investigation into the radiofluorination of the N-heterocyclic carbene (NHC) phosphorus(V) fluoride derivatives 1 and 2, see FIG. 2. Compound 1 was synthesized as described in the literature. To access compound 2, the potassium salt of the known anion [PF.sub.5Ph].sup.+[48] was first synthesized via the one pot oxidation of PPhCl.sub.2 using bromine in the presence of KF and structurally characterized (FIG. 4 and FIG. 5). This salt, whose .sup.19F and .sup.31P NMR spectra are consistent with those of previously reported for other [PF.sub.5Ph].sup. salts [48], was successfully converted into the target compound 2 in 68% yield by addition of n-Bali at 78 C. to a mixture of imidazolium salt and K[PF.sub.5Ph] (FIG. 3). The .sup.19F NMR analysis of the crude mixture at room temperature after n-BuLi addition shows a doublet (J.sub.PF=849 Hz) for 2 at 43.9 ppm and a cis product with an approximate ratio 1:1 (Scheme 1). The cis adduct is characterized by three .sup.19F resonances: a doublet of virtual triplet at 57.6 ppm, (J.sub.PF=783 Hz, J.sub.FF=40 Hz) and two doublet of doublet of triplet at 43.2 ppm, (J.sub.PF=699 Hz, J.sub.FF=49 Hz, J.sub.FF=40 Hz) and at 61.0 ppm, (J.sub.FF=838 Hz, J.sub.FF=49 Hz, J.sub.FF=40 Hz) with a fluorine integration of 2:1:1 respectively. Heating this mixture at 66 C. for 26 h shows isomerisation of cis product into the trans product 2 (FIG. 6 and FIG. 7). Compound 2 is further characterized by a .sup.31P NMR resonance at 141.1 ppm split into a quintet (J.sub.PF=849 Hz). The .sup.1H NMR spectrum shows a characteristic singlet for the methyl substituents while .sup.13C NMR shows two doublet of quintet at 150.0 ppm (J.sub.CF=43 Hz, J.sub.CF=297 Hz) and 159.8 ppm (J.sub.CF=71 Hz, J.sub.CF=334 Hz) corresponding to the phenyl ipso-carbon and carbene carbon, respectively. These assignments align with those reported for other NHCPF.sub.4Ph derivatives [49]. The structure of 2 has been confirmed by X-ray diffraction which shows that the carbene-phosphorus C(1)-P(1) distance (1.898(2) A) is only slightly longer than the C(6)-P(1) bond (1.839(2)) involving the phenyl group (FIG. 3).

    [0079] The hydrolytic stability study of 1 and 2 was evaluated using a previously published method [50]. The compounds were dissolved in D.sub.2O-CD.sub.3CN (8/2 vol) at pH 7.5 ([phosphate buffer]=500 mM) and the hydrolysis reaction was monitored by .sup.19F NMR spectroscopy. While salt K[PF.sub.5Ph] shows a complete hydrolysis in less than 5 min, both carbenes adducts 1 and 2 are highly water stable. Compound 2 undergoes a slow hydrolysis to afford free fluoride and phosphate with a pseudo-first order rate constant (k.sub.obs) of 2.310.sup.5 min.sup.1 (FIG. 8, Table 1). Surprisingly, free fluoride signal for 1 was not observed after five days indicating that 1 can be considered as eternal (FIG. 9). It is more stable than the BF.sub.3 analogue which shows a hydrolytic rate constant (k.sub.Obs) of 1.210.sup.6 min.sup.1 under the same conditions [41].

    TABLE-US-00001 TABLE 1 Hydrolytic kinetics of 2. The values provided for int [F.sup.] and int [2] correspond to the integration of the corresponding .sup.19F NMR signal. Time [2]/([2] + [F.sup.]) [2]/([2] + [F.sup.]) (min) int[F.sup.] int[2] exp calc ln[2] 0 0 100 1.000 1.000 0.000 5 2 100 0.979 1.000 0.021 1035 5 100 0.954 0.976 0.048 2940 10 100 0.912 0.933 0.092 8380 22 100 0.816 0.821 0.203 12715 37 100 0.729 0.742 0.317 20050 63 100 0.612 0.624 0.491 28759 99 100 0.502 0.509 0.690

    [0080] As illustrated in Table 2, the radiochemical yields (RCY) of 1 which was calculated based on the radio-activity of the isolated product and the starting radio-activity are quite low (4-6% decay corrected RCY). These low yields originate from the stability of the PF bonds which impedes the .sup.18F-.sup.19F isotopic exchange process. It was found that increasing the reaction temperature leads to higher radiochemical yield (Table 2, entries 1-3). However, when a high reaction temperature (100 C.) was employed, the radio-peak of [.sup.18F]-1 and the UV-peak of I were not observed by HPLC suggesting precursor decomposition (FIG. 10 A-B). Similar issues were encountered in the radiofluorination of 2, for which all efforts proved unsuccessful including those involving different types of activators such as SnCl.sub.2, SnCl.sub.4, TMSOTf, HCl, and KHF.sub.2.

    TABLE-US-00002 TABLE 2 Radiosynthetic results for [.sup.18F]- 1 [1] SnCl.sub.4 Temp. Time SA.sup.a RCY.sup.b Entry (mol) (equiv.) ( C.) (Min) (mCi/mol) (%) 1 0.9 5 25 10 No [.sup.18F]-1 observed 2 0.9 5 60 10 22.7 4.3 3 0.9 5 80 10 32.5 6.6 .sup.aSpecific activity is determined by dividing the product activity by the amount of the product (based on the integration of UV-HPLC and compare with the UV chromatogram of the standard). .sup.bRCY = activity of the isolated product/starting .sup.18F activity. All yields are decay corrected.

    TABLE-US-00003 TABLE 3 Radiosynthetic results for [.sup.18F]-1 Post Sep-Pak Pre Sep-Pak purification purification Post HPLC Starting Amount MeCN solution Amount activity of [1] Volume SnCl.sub.4 Temp Time Activity volume of [1] Activity Entry (mCi) (mol) (L) (eq) ( C.) (min) (mCi) (mL) (mol) (mCi) 1 98.8 0.9 30 5 25 10 No [.sup.18F]- 1 observed 2 390 0.9 30 5 60 10 18 1 0.74 16.8 3 370 0.9 30 5 80 10 27.7 1 0.75 24.4 4 102.5 0.9 30 5 100 30 No [.sup.18F]- 1 observed

    [0081] The stability of [.sup.18F]-1 was first investigated in phosphate buffer solution (1PBS). [.sup.18F]-1 displayed >98% radiochemical purity even after an incubation time of 3 hours. This result suggested that [.sup.18F]-1 might be extremely stable under physiological condition. The stability of [.sup.18F]-1 was further evaluated in a murine model. The probe [.sup.18F]-1 (0.1 mCi) was injected into female nude mice and static microPET scans were obtained at 3 hours after the injection. As shown in FIG. 11 A-B, the microPET/CT images showed an obvious localization in the bladder indicating that [.sup.18F]-1 was cleared through the urinary track. No bone uptake was observed suggesting that the [.sup.18F]-fluoride release was insignificant even 3 hours post-injection.

    [0082] In conclusion, a phosphorus-based [.sup.18F]-radiotracer was synthesized. Owing to Coulombic effects between the imidazolium and phosphate moieties, this probe is remarkably resistant to hydrolysis. Although it is not necessary to understand the mechanism of an invention, it is believed that such probes can be radiolabeled by isotopic exchange when SnCl.sub.4 is used as an acidic promoter and can be imaged using PET for as long as three hours post injection. It is further believed that it is possible that there are additional ways to functionalize this adduct such that it can be used as a prosthetic group for targeted tissue and disease imaging.

    EXAMPLES

    [0083] The following examples are provided in order to demonstrate and further illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof.

    Example 1

    Experimental: General Procedures

    [0084] 1-Methylimidazole and methyl iodide, from Alfar Aesar, Sodium acetate was purchased from Mallinckrodt. Dichlorophenylphosphine, and bromine was purchased from Strem Chemicals. Potassium fluoride was purchased from Sigma Aldrich. All chemicals were used without further purification. Potassium fluoride was stored in an oven at 100 C. and dried under vacuum at 100 C. for 2 h before use. Solvents were dried by passing through an alumina column (CH.sub.2Cl.sub.2), refluxing under N.sub.2 over Na (Et.sub.2O and THF), refluxing under N.sub.2 over CaH.sub.2 and stored on 3 molecular sieves (CH.sub.3CN). Electrospray mass spectra were acquired on a MDS Sciex API QStar Pulsar. NMR spectra were recorded on a Varian Unity Inova 300 NMR and an Inova 5008 spectrometer at ambient temperature. Chemical shifts are given in ppm, and are referenced to residual .sup.1H and .sup.13C solvent signals as well as external BF.sub.3-Et.sub.2O (.sup.19F NMR) and H.sub.3PO.sub.4 (.sup.31P NMR).

    [0085] Previously published procedures were followed for compound 1 [51] and dimethylimidazolium iodide [52].

    Example 2

    Procedure for KPF.SUB.5.Ph and (NHC)PF.SUB.4.Ph (2) Synthesis

    [0086] KPF.sub.5Ph.

    [0087] Bromine (6.2 mL, 120 mmol) was added to a mixture of potassium fluoride (42 g, 723 mmol) and dichlorophenylphosphine (16.3 mL, 120 mmol) in acetonitrile (250 mL), which caused instantaneously a color change to yellow. The mixture was stirred at room temperature for 18 h to give a dark brown a solution with a white precipitate. Volatiles were evaporated under vacuum, extract with acetonitrile (2100 mL), and filtered. Evaporation of the solvent was followed by washing of the solid residue with EtO (250 mL), and drying under vacuum gave the desired product as a white powder (26.7 g, 92%). X-ray quality crystals were obtained from a saturated solution in acetonitrile at 18 C. This compound must be protected from ambient atmosphere, because it appeared to be hydrolysed: the white powder may become an acidic oil (pH<2) after 15 min exposure to air. .sup.1H NMR (500 MHz, CD.sub.3CN): 7.23-7.30 (m, 3H, H.sup.ortho+para), 7.63-7.68 (m, 2H, H.sup.meta). .sup.31P NMR (202 MHz, CD.sub.3CN): 137.0 (quintd, J.sub.PF=673 Hz, J.sub.PF=822 Hz). .sup.19F NMR (470 MHz, CD.sub.3CN): 58.4 (dd, 4F, J.sub.FF=822 Hz, J.sub.FF36 Hz), 61.1 (dquint, 1F, J.sub.FP=673 Hz, J.sub.FF=36 Hz), see FIG. 13. .sup.13C NMR (125 MHz, CD.sub.3CN): 127.79 (d, J.sub.CF=19 Hz, CH.sup.ortho), 127.90 (m, CH.sup.meta), 131.47 (dquint, J.sub.CF=4.2 Hz, J.sub.CF=9.3 Hz, CH.sup.para), 150.31 (dquint, J.sub.CF=306 Hz, J.sub.CF=45 Hz, C.sup.ipso), HRMS (ESI) calcd for [M].sup.+: 203.0063, found: 203.0049. Anal. Calcd. for C.sub.6H.sub.5F.sub.5KP (242.17): C, 29.76; H, 2.08. Found: C, 29.91; H, 1.98.

    Example 3

    Synthesis of (NHC)PF.SUB.4.Ph, (2)

    [0088] A 2.2 M solution of n-BuLi in hexane (4.54 mL, 10 mmol) was added dropwise at 78 C. to a heterogeneous mixture of KPF.sub.5Ph (2.42 g, 10 mmol) and dimethylimidazolium iodide (2.24 g, 10 mmol) in THF (50 mL). The solution was slowly reheated at room temperature then heated for 18 h at 65 C. The volatiles were evaporated under vacuum, the solid residue was washed with several portions of water (100 mL), filtered, washed with a small portion of EtOH (10 mL), and dried under vacuum to give a white powder (1.83 g, 65%). X-ray quality crystals were obtained by slow evaporation of a solution of acetonitrile under ambient atmosphere. .sup.1H NMR (300 MHz, CD.sub.3CN): 3.97 (s, 6H, CH.sub.3), 7.09 (d, J.sub.PH=3.1 Hz, 2H, CH.sup.NHC), 7.24-7.31 (m, 3H, H.sup.Ph-ortho+para), 7.65-7.70 (m, 2H, H.sup.Ph-meta). .sup.31P NMR (121 MHz, CD.sub.3CN): 141.1 (quint, J.sub.PF=849 Hz). .sup.19F {.sup.1H} NMR (282 MHz, CD.sub.3CN): 43.9 (d, J.sub.FP=849 Hz). .sup.13C {.sup.1H} NMR (75 MHz, CD.sub.3CN): 39.10 (quint, J.sub.CF=4.4 Hz, CH.sub.3), 123.09 (d, J.sub.CP=9.9 Hz, CH.sup.NHC), 127.93 (d, J.sub.CP=20.3 Hz, CH.sup.Ph-para), 128.26 (d, J.sub.CF=4.0 Hz, CH.sup.Ph-meta), 131.49 (dquint, J.sub.CF=4.0 Hz, J.sub.CP=11.3 Hz, CH.sup.Ph-para), 150.01 (dquint, J.sub.CF=43 Hz, J.sub.CP=297 Hz, CH.sup.Ph-iso), 159.84 (dquint, J.sub.CF=71 Hz, J.sub.CF=334 Hz, C.sub.q.sup.NHC). HRMS (ESI+) calcd for [MF].sup.+: 261.0768, found: 261.0640. Anal. Calcd. for C.sub.11H.sub.13F.sub.4N.sub.2P (280.21): C, 47.15; H, 4.68. Found: C, 47.05; H, 4.57.

    Example 4

    Crystal Structure Determinations.

    [0089] The crystallographic measurement of KPF.sub.5Ph (FIG. 5) and 2 (FIG. 4) were performed using a Bruker APEX-II CCD area detector diffractometer, with graphite-monochromated Mo-K radiation (=0.71069 ). A specimen of suitable size and quality was selected and mounted onto a nylon loop. The semi-empirical method SADABS was applied for absorption correction. The structure was solved by direct methods, and refined by the full-matrix least-square method against F2 with the anisotropic temperature parameters for all non-hydrogen atoms. All H atoms were geometrically placed and refined using the riding model approximations. Data reduction and further calculations were performed using the Bruker SAINT+ and SHELXTL NT program packages. Table 4 includes crystal data collection and refinement parameters for compounds 2 and KPF.sub.5Ph. Table 5 includes selected distances () and angles () for KPF.sub.5Ph.

    TABLE-US-00004 TABLE 4 Crystal data collection and refinement parameters for compounds 2 and KPF.sub.5Ph. 2 KPF.sub.5Ph chemical formula C.sub.11H.sub.13F.sub.4N.sub.2P C.sub.32H.sub.32F.sub.20K.sub.4N.sub.4P.sub.4 Fw 280.2 1132.9 T (K) 110 (2) 110 (2) wavelength () 0.71073 0.71073 space group P21/n P21/n a () 7.5298 (13) 21.180 (3) b () 11.1769 (19) 8.8602 (13) c () 14.477 (3) 24.220 (4) (deg) 90 90 (deg) 104.313 (2) 102.725 (2) (deg) 90 90 Z 4 4 V (.sup.3) 1180.6 (4) 4433.4 (11) .sub.calcd (g cm.sup.3) 1.577 1.697 (mm.sup.1) 0.268 0.662 range (deg) 2.33-28.29 1.97-27.25 R1.sup.a [I > 2(I)] 0.0352 0.0418 wR2.sup.b [I > 2(I)] 0.0954 0.0952 R1 [all data] 0.0425 0.0594 wR2 [all data] 0.1004 0.1036 GOF 1.069 1.036 .sup.aR.sub.1 = (||F.sub.o| |F.sub.c||)/|F.sub.o| .sup.BWR.sub.2 = {[WFo.sup.2 Fc.sup.2).sup.2]/[WFo.sup.2).sup.2]}.sup.1/2

    TABLE-US-00005 TABLE 5 Selected distances () and angles () for KPF.sub.5Ph. Molecule 1 Molecule 2 Molecule 3 Molecule 4 PC P.sub.1C.sub.1 = 1.837(3) P.sub.2C.sub.7 = 1.829(3) P.sub.3C.sub.13 = 1.831(3) P.sub.4C.sub.27 = 1.833(3) PF.sub.trans P.sub.1F.sub.1 = 1.6391(16) P.sub.2F.sub.6 = 1.5857(19) P.sub.3F.sub.11 = 1.6512(17) P.sub.4F.sub.16 = 1.6323(16) PF.sub.cis P.sub.1F.sub.2 = 1.6187(17) P.sub.2F.sub.7 = 1.6460(15) P.sub.3F.sub.12 = 1.6064(17) P.sub.4F.sub.17 = 1.6394(15) P.sub.1F.sub.3 = 1.6121(16) P.sub.2F.sub.8 = 1.6287(16) P.sub.3F.sub.13 = 1.6132(16) P.sub.4F.sub.18 = 1.6203(15) P.sub.1F.sub.4 = 1.6288(17) P.sub.2F.sub.9 = 1.6318(16) P.sub.3F.sub.14 = 1.6292(16) P.sub.4F.sub.19 = 1.6281(15) P.sub.1F.sub.5 = 1.6263(16) P.sub.2F.sub.10 = 1.6367(17) P.sub.3F.sub.15 = 1.6236(17) P.sub.4F.sub.20 = 1.6321(15) CPF.sub.trans C.sub.1P.sub.1F.sub.1 = C.sub.7P.sub.2F.sub.6 = C.sub.13P.sub.3F.sub.11 = C.sub.27P.sub.4F.sub.16 = 178.84(11) 178.68(12) 179.15(12) 179.70(11) CPF.sub.cis C.sub.1P.sub.1F.sub.2 = C.sub.7P.sub.2F.sub.7 = C.sub.13P.sub.3F.sub.12 = C.sub.27P.sub.4F.sub.17 = 92.63(10) 92.60(10) 93.57(11) 92.45(10) C.sub.1P.sub.1F.sub.3 = C.sub.7P.sub.2F.sub.8 = C.sub.13P.sub.3F.sub.13 = C.sub.27P.sub.4F.sub.18 = 93.02(10) 92.86(10) 93.50(11) 92.92(10) C.sub.1P.sub.1F.sub.4 = C.sub.7P.sub.2F.sub.9 = C.sub.13P.sub.3F.sub.14 = C.sub.27P.sub.4F.sub.19 = 91.83(10) 92.32(10) 92.11(10) 92.78(10) C.sub.1P.sub.1F.sub.5 = C.sub.7P.sub.2F.sub.10 = C.sub.13P.sub.3F.sub.15 = C.sub.27P.sub.4F.sub.20 = 93.10(10) 92.72(10) 92.80(10) 93.03(10)
    Complete details of the X-ray analyses reported herein have been deposited at The Cambridge Crystallographic Data Centre (CCDC 1504580 (KPF.sub.5Ph), 1504579 (2)). This data can be obtained free of charge via world wide web ccdc.cam.ac.uk/data_request/cif.

    Example 5

    Kinetic Studies of the Hydrolysis Reactions for 1 and 2

    [0090] A sample of I was dissolved in a mixture of 0.2 mL CD.sub.3CN and 0.8 mL D.sub.2O phosphate buffer solution (pH 7.5, 500 mM) while a sample of 2 (5 mg), was dissolved in a mixture of 0.3 mL dmso-d6, 0.63 mL H.sub.2O phosphate buffer (pH 7.5, 500 mM) and 70 mg of Triton X-100. The .sup.19F NMR spectra of I and 2 were collected periodically. The decomposition of 2 were monitored by integration of the decreasing of the signal of 2 in conjunction with the increasing signal corresponding to free F. The rate constant, k.sub.obs, was calculated using a well-established NMR method reported in the literature[50]. This method was based on the fact that that the concentration of 2 is proportional to the .sup.19F NMR integration of the signal of 2 divided by the sum of the integration of the signal of 2 and the free fluoride signal. For convenience, the value of the integration of 2 was arbitrarily set at 100 and the free fluoride integration determined. The resulting data is provided in Table 1.

    Example 6

    Radiochemistry Experiment

    [0091] All chemicals were purchased in analytical grade and used without further purification. Analytical reversed-phase high-performance liquid chromatography (HPLC) was performed on a SPD-M30A photodiode array detector (Shimadzu) and model 105S single-channel radiation detector (Carroll & Ramsey Associates) using a Gemini 5 C18 column (2504.6 mm). The flow was set to 1 mL/min. The mobile phase was programmed to change from 95% solvent A and 5% solvent B (0-2 min) to 5% solvent A and 95% solvent B at 22 min, where solvent A is 0.1% TFA in water and solvent B is 0.1% TFA in acetronitrile. See FIGS. 12A&B.

    Example 7

    Radiolabeling

    [0092] The radiolabeling reactions were performed using the following protocol. Compound 1 (0.9 mol) was mixed with SnCl.sub.4 (5 equiv.) in 30 L of anhydrous MeCN. The resulting solution was then combined with [.sup.18F]-tetra-n-butylammonium fluoride (TBAF) in MeCN. After incubating at reaction temperature (room temperature, 60 C., 80 C., or 100 C.) for 10 min, the reaction was quenched by adding 10 mL of water. The mixture was passed through a Sep-Pak cartridge (Sep-Pak Plus tC18) and washed with another 10 mL of water to remove all Sn-by-products. The radiolabeled derivative [.sup.18F]-1 was eluted off the cartridge by 1 mL of MeCN.

    Example 8

    In Vitro Stability Test

    [0093] After HPLC purification, [.sup.18F]-1 was re-injected into HPLC for a radio profile standard. Then, the probe was added with 10PBS to reconstruct the solution to IX PBS and 0.1 N NaOH to adjust pH to 7, respectively. After 1 hour and 3 hours incubation, a fraction of [.sup.18F]-1 was injected into HPLC. The radio purity was calculated based on the integration of the product peak and other minor peaks.

    Example 9

    MicroPET Imaging

    [0094] MicroPET imaging were acquired at 3 h post injection. For PET image acquiring, a female nude mouse was injected with 0.1 mCi of [.sup.18F]-1 via the tail vein. At 3 hour post injection, the mouse was anesthetized using isoflurane (2% in oxygen), then placed into imaging chambers equipped with a heated coil to maintain body temperature and gas anesthesia. The static microPET acquisitions were then achieved and reconstructed for analysis.

    [0095] Thus, specific compositions and methods of probes for .sup.18F positron emission tomography imaging have been disclosed. It should be apparent, however, to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. Moreover, in interpreting the disclosure, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms comprises and comprising should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced.

    [0096] Although the invention has been described with reference to these preferred embodiments, other embodiments can achieve the same results. Variations and modifications of the present invention will be obvious to those skilled in the art and it is intended to cover in the appended claims all such modifications and equivalents. The entire disclosures of all applications, patents, and publications cited above, and of the corresponding application are hereby incorporated by reference.

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