WO2015134467A1 - Methods and compositions for direct radioactive labeling of bio-active molecules and building blocks - Google Patents

Abstract

Methods of direct radioactive labeling a carbon containing compound having an sp3 C-H bond are provided. Methods of carrier-free 18F fluorination of a carbon containing compound mediated by manganese salen complexes or manganese porphyrin complexes comprising weakly coordinated anions as axial ligands are provided. Methods of "dry-down" free radioactive labeling of a carbon containing compound having an sp3 C-H bond are provided. The radioactively labeled products of the methods are provided.

Description

[0001] METHODS AND COMPOSITIONS FOR DIRECT

RADIOACTIVE LABELING OF BIO-ACTIVE MOLECULES AND BUILDING BLOCKS

[0002] This application claims the benefit of U.S. Provisional Application

No. 61/948,446, filed March 5, 2014, which is incorporated herein by reference as if fully set forth.

[0003] This invention was made with government support under Grant No.

CHE-1148597 awarded by the National Science Foundation and Grant No. DE- SC0001298 awarded by the U.S. Department of Energy. The government has certain rights in this invention.

[0004] FIELD

[0005] The disclosure relates to one-step carrier-free (¹⁸F) fluorination of carbon containing compounds using fluoride ions.

[0006] BACKGROUND

[0007] A recent upsurge in fluorination chemistry has revealed a number of novel ¹⁸F labeling methods, including preparation of [¹⁸F]fluoroaromatics through aryl iodonium salts, Pd-catalyzed allylic fluorination with [¹⁸F]fluoride, the preparation of [¹⁸F]4-fluorophenols via the oxidative fluorination of A-tert- butylphenols, aromatic ¹⁸F labeling through Pd^IV or Ni¹¹ complexes, and copper- catalyzed ¹⁸F labeling of aryltrifluoromethyl groups (Pike, V. W.; Aigbirhio, F. I. J. Chem. Soc, Chem. Commun. 1995, 2215; Ross, T. L. et al., J. Am. Chem. Soc. 2007, 129, 8018; Hollingworth, C. et al., Angew. Chem. Int. Ed. 2011, 50, 2613; Gao, Z. et al., Angew. Chem. Int. Ed. 2012, 51, 6733; Lee, E. et al., J. Am. Chem. Soc. 2012, 134, 17456; Lee, E. et al., Science 2011, 334, 639; Huiban, M. et al., J Nat. Chem. 2013, 5, 941).

[0008] Some of these methods have been scaled up and optimized for high specific activity imaging applications, while others have yet to be demonstrated in an imaging context due to practical limitations of the methodologies (Kamlet, A. S. et al., PLoS ONE 2013, 8, 10).

[0009] Of a particular interest is application of fluorination chemistry and

¹⁸F labeling methods for positron emission tomogramphy (PET). PET is a molecular imaging modality that has wide applications in clinical oncology, cardiology and neurology as well as basic biomedical research (Phelps, M. E. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 9226; Miller, P. W. et al., Angew. Chem. Int. Ed. 2008, 47, 8998; Ametamey, S. M. et al., Chem. Rev. 2008, 108, 1501). The characteristics that set PET apart from other imaging techniques, such as MRI, X-radiography or ultrasound, is its ability for non-invasive imaging of in vivo events at a molecular level. The unique feature of PET that gives it a high degree of molecular diversity is the use of radioactive tracers containing a positron- emitting isotope. Among all PET radioisotopes, ¹⁸F is the most widely used and clinically relevant radionuclide (Tredwell, M.; Gouverneur, V. Angew. Chem. Int. Ed. 2012, 51, 11426). Furthermore, fluorinated derivatives of known drugs often show stronger binding to target sites, lower metabolic burden and higher bioavailability (Purser, S. et al., Chem. Soc. Rev. 2008, 37, 320; Muller, K. et al., Science 2007, 317, 1881). By far the most prominent radiotracer to date is [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG), which has dominated PET oncology field for over 20 years (Wood, K. A. et al., Clin. Oncol. 2007, 19, 237).

[0010] Despite the great success of PET imaging in certain clinical and research domains, the development of new radiotracers remains a formidable challenge (Agdeppa, E. D.; Spilker, M. E. AAPS J. 2009, 11, 286). Currently, there are only seven FDA-approved PET tracers, three of which are simple radionuclides (Vallabhajosula, S. et al., Semin. Nucl. Med. 2011, 41, 246; Koo, J.; Byun, Y. Arch. Pharm. Res. 2013, 36, 1178). It is impossible to predict whether a particular radiolabeled molecule will exhibit the required in vivo characteristics of a radiotracer (specific, saturable binding, appropriate binding kinetics, and appropriate metabolic fate). Thus, high throughput assessment of potential radiotracers would be highly advantageous to increase the rate of discovery. One main challenge tempering PET throughput stems from constraints on applicable synthetic methods for radiolabeling and the synthesis of precursors (Mach, R. H.; Schwarz, S. W. PET Clinics 2010, 5, 131). Due to their short half-lives, PET radioisotopes typically must be incorporated into tracer molecules at a late stage of the overall synthesis process. Combined with other constraints, including solvent compatibilities, low reaction concentrations and the need for rapid process steps such as product purification, PET radiotracer synthesis has a very limited toolbox of chemical reactions. For ¹⁸F labeling, the majority of the radiotracers and radiotracer candidates are synthesized through nucleophilic ¹⁸F- substitution (Le Bars, D. J. Fluorine Chem. 2006, 127, 1488).

[0011] SUMMARY

[0012] In an aspect, the invention relates to a method of direct radioactive labeling of a carbon containing compound having an sp3 C-H bond. The method includes combining a carbon containing compound having an sp3 C-H bond, a fluorine radioisotope, a fluorinating catalyst, a solvent, and an oxidant. The fluorinating catalyst is a manganese salen complex comprising a weakly coordinated anion as an axial ligand or a manganese porphyrin complex comprising a weakly coordinated anion as an axial ligand.

[0013] BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The following detailed description of the preferred embodiments of the present invention will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It is understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown. In the drawings:

[0015] FIGS. 1A and IB illustrate approaches for labeling molecules with

¹⁸F. FIG. 1A illustrates traditional approaches that require multistep synthesis of pre-activated labeling precursors, which is time and resource consuming. FIG. IB illustrates direct C-H ¹⁸F-fluorination strategy that enables direct and efficient labeling of parent molecules. [0016] FIG. 2 illustrates direct ¹⁸F labeling of aliphatic C-H bonds of substrates with a variety of functional groups. Reported radiochemical yields (RCYs) are decay-corrected radiochemical yields and are averaged over n experiments.

[0017] FIG. 3 illustrates compounds provided in compositions and methods herein and fluorinated by methods herein.

[0018] FIG. 4A - 4H illustrates potential manganese salen catalyzed benzylic C-H fluorination substrates.

[0019] FIG. 5 illustrates dry- down free procedure for the automated synthesis of ¹⁸F-celestolide.

[0020] FIG. 6A illustrates proposed mechanism for ¹⁸F labeling of benzylic

C-H bonds catalyzed by a manganese salen catalyst.

[0021] FIG. 6B illustrates ¹⁸F labeling products of celestolide.

[0022] FIG. 6C illustrates energy landscape of fluorine transfer from F-

Mn^IV-OH intermediate (34) to benzyl radical.

[0023] FIGS. 7A - 7H illustrate examples of the radio-TLC scans of different compounds described herein. FIG. 7A illustrates the radio-TLC scan for Compound 2. FIG. 7B illustrates the radio-TLC scan for Compound 23. FIG. 7C illustrates the radio-TLC scan for Compound 25. FIG. 7D illustrates the radio- TLC scan for Compound 27. FIG. 7E illustrates the radio-TLC scan for Compound 28. FIG. 7F illustrates the radio-TLC scan for Compound 29. FIG. 7G illustrates the radio-TLC scan for Compound 30. FIG. 7H illustrates the radio- TLC scan for Compound 31.

[0024] FIGS. 8 - 36 illustrate radio-HPLC characterization of Compounds 2

-19 and 21 - 31.

[0025] FIG. 37A - 37B illustrate detection and enantoselectivity of labeling products of celestolide chiral radio HPLC analysis. FIG. 37A illustrates products of the reaction catalyzed by (R, R)-Mn(salen)OTs. FIG. 37B illustrates products of the reaction catalyzed by (S, S)-Mn(salen)OTs.

[0026] FIGS. 38 - 59 illustrate radio-HPLC characterization of Compounds

32 - 35, 37, 39 - 46, 47, 50 - 51, 53 - 55 and 59 - 61. [0027] FIG. 60 illustrates substrates and bioactive molecules used for a manganese salen mediated ¹⁸F-difluoroalkylation reaction described herein.

[0028] DETAILED DESCRIPTION OF THE PREFERRED

EMBODIMENTS

[0029] Certain terminology is used in the following description for convenience only and is not limiting. The words "a" and "one," as used in the claims and in the corresponding portions of the specification, are defined as including one or more of the referenced item unless specifically stated otherwise. The phrase "at least one" followed by a list of two or more items, such as "A, B, or C," means any individual one of A, B or C as well as any combination thereof.

[0030] Catalysts and methods of use thereof are discussed in U.S. Patent

No. 6,002,026; U.S. Publication No.20130209573; and U.S. Publication No. 20150031768, which are incorporated herein by reference as if fully set forth. The embodiments described herein extend the knowledge of catalysts and methods of use thereof. One or more of the catalysts in U.S. Patent No. 6,002,026; U.S. Publication No. 20130209573; and U.S. Publication No.20150031768 may be utilized in an embodiment herein as a halogenating catalyst or a fluorinating catalyst if modified to include manganese and a weakly coordinating axial ligand, as described herein with reference to porphyrin and salen catalysts.

[0031] An embodiment includes a method of direct radioactive labeling of a carbon containing compound having an sp3 C-H bond. The method may include combining a carbon containing compound having an sp3 C-H bond, a fluorine radioisotope, a fluorinating catalyst, a solvent and an oxidant. The fluorinating catalyst may be a manganese salen complex comprising a weakly coordinated anion as an axial ligand or a manganese porphyrin complex comprising a weakly coordinated anion as an axial ligand.

[0032] An embodiment includes a method of direct radioactive labeling of a carbon containing compound having an sp3 C-H bond. The method comprises reacting the carbon containing compound having an sp3 C-H bond with a fluorine radioisotope in the presence of a fluorinating catalyst. The reaction may also include an oxidant. The fluorinating catalyst may be a manganese salen complex comprising a weakly coordinated anion as an axial ligand or a manganese porphyrin complex comprising a weakly coordinated anion as an axial ligand. Non-limiting examples follow.

[0033] In an example, 17 mg of Mn(salen)OTs (0.022 mmol) was combined with substrate (0.25 mmol) in a 4 ml vial and stirred before labeling. An aqueous [¹⁸F]fluoride solution was obtained from the cyclotron. A portion of this solution (40 - 50 μΐ,, 4 - 5 mCi) was loaded to an CHROMAFIX® PS cartridge to obtain a washed, purified and diluted (~20x) [¹⁸F] fluoride solution. Twenty five microliters of the resulting washed [¹⁸F]fluoride solution (125 - 150 μϋί) was diluted with 3.0 mL acetone to obtain an [¹⁸F]fluoride acetone solution. A portion of this [¹⁸F] fluoride acetone solution (0.6 mL) was added to the vial containing the catalyst and the substrate. The resulting solution was stirred for 1 minute at room temperature. Then 25 mg (0.25 mmol) iodosylbenzene (PhIO) was added to the solution, and the vial was capped and stirred at 50 °C for 10 minutes. After 10 minutes, an aliquot of the reaction mixture was taken and spotted on a silica gel TLC plate. The plate was developed in an appropriate eluent and scanned with a Bioscan AR-2000 Radio TLC Imaging Scanner.

[0034] In another example, a 4 mL vial was charged with substrate (0.33 mmol) and stirred. An aqueous [¹⁸F] fluoride solution was obtained from the cyclotron. A portion of this solution (40 - 50 μL, 4 - 5 mCi) was loaded onto an CHROMAFIX® PS cartridge. Then the cartridge was washed with 2 mL anhydrous acetonitrile three times. The [¹⁸F]fluoride was released using 0.8 mL acetone solution of Mn(salen)OTs (23 mg, 0.030 mmol)(> 90% radioactivity being eluted). The obtained solution was added to the vial containing the substrate and 60 mg of PhIO was added. The vial was capped and stirred at 50 °C for 10 min. After 10 minutes, aliquot of the reaction mixture was taken and spot on a silica gel TLC plate. The plate was developed in an appropriate eluent and scanned with a Bioscan AR-2000 Radio TLC Imaging Scanner.

[0035] A schematic representation of a method of direct radioactive labeling herein is illustrated in FIG. IB. Referring to this figure, the hydrogen "H" included in the parent molecule is replaced by a fluorine radioisotope ¹⁸F and to produce the fluorinated analog. The reaction is catalyzed by a manganese salen complex Mn(salen)OTs in the presence of an oxidant.

[0036] In an embodiment, the fluorinating catalyst may include at least one catalyst selected from manganese salen complexes or manganese porphyrin complexes that include one or more weakly coordinated anions as axial ligands. As used herein, the term "weakly coordinated anions" refers to anions that interact weakly with cations.

[0037] Examples of the weakly coordinated anions include but are not limited to toluenesulfonate (OTs), trifluoromethanesulfonate (triflate or OTf), perchlorate, (CIO4), tetrafluoroborate (BF4), hexafluorophosphate (PFe), BARF ([B[3,5-(CF3)2C₆H₃] 4]), hexafluorophosphate (PF₆), hexafluoroantimonate(V) (SbFe), methanesulfonate (OMs), or 4- nitrobenzenesulfonate. The skilled artisan would understand that all relevant anions have the expected anion charge, but the charges are not shown for convenience.

[0038] The fluorinating catalyst may be a manganese salen complex. See

Scheme 1, below. As used herein, salen refers to Ν,Ν'- bis(salicylidene)ethylenediamine. The manganese salen complex may be but is not limited to salenmanganese trifluoromethanesulfonates (hereinafter "Mn(salen)OTf'), salenmanganese toluenesulfonates (hereinafter "Mn(salen)OTs"), or manganese salen perchlorates (hereinafter "Mn(salen)C104"). The manganese salen complex may catalyze direct C-H ¹⁸F radioactive labeling of the carbon containing compounds at benzilic positions. Example 1 herein describes a variety of bioactive molecules that have been successfully labeled with radiochemical conversions (RCCs) up to 70%.

[0039] In an embodiment, the fluorinating catalyst may be a manganese porphyrin complex. The manganese porphyrin complex may be any one of the manganese porphyrin complexes shown in Scheme 1 below.

Scheme 1. Salen and manganese porphyrin complexes optimized for direct ¹⁸F fluorination of unactivated aliphatic C-H bonds.

[0040] Scheme 1 illustrates a salen manganese complex (1) and a manganese porphyrin complex that includes four R- groups in the positions 5, 10, 15 and 20 of the porphyrin ring. An R-goup therein may be one or more of mesityl, phenyl, difluorophenyl, dichlorophenyl, or pentafluorophenyl groups. Referring to this scheme, if all of the R groups are substituted with mesityl groups, the resulting structure 2 is tetramesitylporphyrinatomanganese toluenesulfonate (hereinafter "Mn(TMP)OTs"). Still referring to Scheme 1, if all of the R groups are substituted with dichlorophenyl groups, the resulting structure 3 is tetra-2,6-dichlorophenylporphyrinatomanganese toluenesulfonate (hereinafter "Mn(TDClPP)OTs"). Still referring to Scheme 1, if all of the R groups are substituted with difluorophenyl groups, the resulting structure 4 is tetra-2,6- difluorophenylporphyrinatomanganese toluenesulfonate (hereinafter "Mn(TDFPP)OTs"). Still referring to Scheme 1, if all of the R groups are substituted with pentafluorophenyl groups, the resulting structure 5 is tetra- 2,3,4,5,6-pentafluorophenylporphyrinatomanganese toluenesulfonate (hereinafter "Mn(TPFPP)OTs").

[0041] In an embodiment, the manganese porphyrin complex may include one or more meso-substituents in the porphyrin ring. The one or more meso- substituents may be substituents in the position 5, 10, 15 or 20 of the porphyrin ring. The one or more meso-substituents may be but are not limited to Mn(TMP)OTs, Mn(TDFPP)OTs, Mn(TDClPP)OTs, Mn(TPFPP)OTs, tetraphenylporphyrinatomanganese toluenesulfonate (hereinafter

"Mn(TPP)OTs"), tetrakis-(l,3-dimethylimidazolium-2-yl)porphyrinatomanganese toluenesulfonate (hereinafter "Mn(TDImP)OTs"), tetrakis(N-methylpyridinium-2- yl) porphyrinatomanganese toluenesulfonate (hereinafter "Mn(2-PyP)OTs"), tetrakis(N-methylpyridinium-4-yl)porphyrinatomanganese toluenesulfonate (hereinafter "Mn(4-PyP)OTs"), or other similar manganese porphyrins.

[0042] In an embodiment, a fluorine radioisotope may be ¹⁸F fluoride ion or a compound including ¹⁸F. The fluorine radioistope may be a carrier-free ¹⁸F fluoride. As used herein, the term "carrier-free" refers to the fluoride that is essentially free from stable isotopes of fluorine ¹⁹F. The carrier-free ¹⁸F fluoride is preferred for radiolabeling because the radioactivity of the fluoride undiluted by non-radioactive ¹⁹F can be higher.

[0043] The ¹⁸F fluoride may be obtained directly from the cyclotron as an aqueous ¹⁸F fluoride solution. The aqueous ¹⁸F fluoride solution may be mixed with a solvent. The solvent may be but is not limited to acetone or acetonitrile or a mixture thereof.

[0044] The oxidant may be at least one of meia-chloroperoxybenzoic acid (mCPBA), idosylbenzene, peroxyacid, alkyl peroxide, peroxy sulfate(oxone), peroxycarbonate, peroxyborate, iodosyl mesitylene, pentafluoro-iodosylbenzene, benzene difluoroiodmane [phenyl-IF2], diacetoxyiodobenzene, 2-iodosylbenzoic acid, 2-(tert-butylsulfonyl)iodosylbenzen, peroxyacetic acid, peroxyphthalic acid, or peroxytungstic acid.

[0045] The carbon containing compound may include an sp3 C-H bond, and is also referred to as a substrate or target herein. Any carbon containing compound having sp3 C-H bond may be the carbon containing compound. Examples of the carbon containing compounds include but are not limited to inhibitors of cyclooxygenase (COX), inhibitors of monoamine oxidase B (MAO-B), inhibitors of phosphodiesterase 10A (PDEIOA), inhibitors of angiotensin- converting enzyme (ACE), bio-messenger molecules, the neurotransmitter dopamine, and the immuno-modulating drug fingolimod. Carbon containing compounds may also include but are not limited to Leucine-derivatives, Valine- derivatives, Leucine dipeptide, Boc-Valine-Luecine methyl ester, tyrosine derivatives, pregabalin LYRICA^®, Boc-Amantidine, flutamide, aminocyclopentane earboxylie acid, ibuprofen, ibuprofen methyl ester, rasagiline, nabumetone, celecoxib analog, papaverine, protected enalaprilat, protected fingolimod, protected dopamine, N-Boc-cinacalcet, JNJ41510417, 5-OH-FPPAT, FEP, Acl703. BMIPP, HAR, flutemetamol, MK-9470, FACPC, CURB, MFES, FES, 2-ME, PHNO, PHNO, fallypride, DMFP, 5-OH-FPPAT, 5-OH-DPAT, NPA, NNC112, SCH, FDA, MNPA, MC113, SA4503, SA6298, BMS-747158-01, PBR28, PBR06, FMPEP, MePPEP, FBzBMS, FBFPA, FEPPA, telmisartan, tacrine, desloratadine, etodolac, cinacalcet, tanshinone IIA, indomethacin, trimethoprim, masoprocol, dubutamine, duloxetine, ondansetron, and benzbromarone. Carbon containing compounds may also include but not limited to simple alkanes; neopentane; toluene; cyclohexane; norcarne; simple hydrocarbons; trans-decalin; 5a-cholestane; sclarolide; 1, 3, 5(10)-estratrien-17-one; (lR,4aS, 8aS)-octahydro- 5,5,8a-trimethyl-l-(3-oxobutyl)-naphtalenone; (1R, 4S, 6S, 10S)-4, 12, 12- trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one; levomethorphan; lupine; 20-methyl- 5alpha(H)-pregnane; isolongifolanone; caryophyllene acetate; N-acetyl- gabapentin methyl ester; acetyl- amanti dine; phthalimido-amantadine; methyloctanoate, and other saturated fatty acid esters; N- acetyl- Lyrica methyl ester; artemisinin, adapalene; finasteride; N-acetyl-methylphenidate; mecamylamine and N-acetyl-mecamylamine; N-acetyl-memantine; phthalimidi- memantine; N- acetyl- Enanapril precursor methyl ester; progesterone; artemisinin; adapalene; dopamine derivative; pregabalin; cholestane; finasteride; methylphenidate derivative; mecamylamine; gabapentin; memantine derivative; gabapentin; isoleucine derivative; pregesterone; tramadol; and (1R, 4aS, 8aS)-5, 5, 8a-trimethyl-l-(3-oxobutyl)octahydronaphthalen-2(lH)-one.

[0046] A carbon containing compound may also be any one of the compounds in FIGS. 4A, 4B or 4C. Arrows in FIGS. 4B and 4C indicate positions that may be halogenated. A carbon containing compound may also include an analog of any carbon containing compound herein. An analog of a carbon containing compound may include substitution of a moiety in the compound for another moiety. The carbon containing compound may be a drug or drug candidate precursor of which non-limiting examples are found in FIGS. 4A, 4B, and 4C.In an embodiment, a carbon containing compound may be any compound illustrated in FIGS. 4D, 4E, 4F, 4G, or 4H, or a precursor thereof. The carbon containing compounds of FIGS. 4D, 4E, 4F, 4G, or 4H include drug molecules and ¹⁸F labeled versions thereof may be PET probes or pharmacokinetic tracers. For each compound in FIGS. 4D, 4E, 4F, 4G, or 4H labelling with a fluorine radioisotope may be at the position circled. The hydrogens circled may be replaced by a fluorine radioisotope by a method herein. An embodiment includes compositions containing radiolabeled versions of any of the compounds of FIGS. 4D, 4E, 4F, 4G, or 4H. Each of these compounds could include stable isotopes or the isotope indicated.

[0047] Embodiments include combining the carbon containing compound, the fluorine radioisotope, the fluorinating catalyst, the solvent and the oxidant in any order.

[0048] In an embodiment, the step of combining may include mixing the carbon containing compound and the fluorinated catalyst to form a first mixture. The step of combining may also include mixing the fluorine radioisotope and the solvent to form a second mixture. The first mixture and the second mixture may be combined; for example, by being added to a vial. An antioxidant may be subsequently added; for example, to the same vial.

[0049] In an embodiment, the step of combining may include mixing the fluorine radioisotope and the solvent to form a first mixture. The first mixture may be added to the fluorinating catalyst to form a second mixture. The second mixture may be added to the carbon containing compound; for example, in a vial. An antioxidant may be subsequently added; for example, to the same vial.

[0050] In an embodiment, a fluorine radioisotope may be¹⁸F. Prior to the step of combining, ¹⁸F may be included in an aqueous solution to form a ¹⁸F- fluoride solution. The fluorine radioisotope may be present in the reaction at sub- stoichiometric amounts. The mole ratio of the carbon containing compound/fluorine radioisotope/fluorinating catalyst/oxidant maybe 1/(10 ¹² - 10" ⁹)/0.1/l. [0051] In an embodiment, the method may include allowing the carbon containing compound, the fluorine radioisotope, the fluorinating catalyst, the solvent and the oxidant to react for 10 minutes to 30 minutes. The reaction may be allowed to proceed from 10 minutes to 15 minutes, from 15 minutes to 20 minutes, from 20 minutes to 25 minutes, and from 25 minutes to 30 minutes. The time period for recation may be in a range between any two integer value between 10 minutes and 30 minutes. The reaction may be allowed to proceed for 10 minutes.

[0052] In an embodiment, the method may include maintaining the carbon containing compound, the fluorine radioisotope, the fluorinating catalyst, the solvent and the oxidant at a temperature of 20°C to 70°C. The temperature may be in a range between any two integer value temperatures selected from 20°C to 70°C. The temperature may be in a range between and including 20°C and 30°C, 30°C and 40°C, 40°C and 50°C, 50°C and 60°C, and 60°C and 70°C. The temperature may be any one integer value temperature selected from those including and between 20°C and 70°C. Temperatures between room temperature and 70°C may be used. The temperature may be any one temperature including and between room temperature and 70°C. Temperatures between 25°C and 70°C may be used. The temperature may be any temperature including and between 25°C and 70°C. The temperature may be 50°C.

[0053] In an embodiment, the carbon containing compound may be added to a concentration from 0.1 mol/L to 0.6 mol/L. The fluorine radioisotope may be added to a concentration from 20 μϋί/ηιΐ to 5 Ci/ml. The fluorinating catalyst may be added to a concentration from 0.01 mol/L to 0.03 mol/L. The solvent may be added at a volume of 0. lmL to lmL. The oxidant may be added to a concentration from 0.05 mol/L to 0.6 mol/L. In an embodiment, the oxidant may be solid and a range from 0.05 mmol to 0.6 mmol may be added to the reaction. Each of the foregoing concentration ranges may be subdivided. The concentration of the carbon containing compound may be subdivided between any two values chosen from 0.1 increments within the described range (endpoints inclusive). The concentration of the fluorine radioisotope may be subdivided between any two values chosen from 20 μϋί increments within the described range (endpoints inclusive). The volume of the solvent may be subdivided between any two values chosen from 0.1 increments within the described range (endpoints inclusive). The concentarion of the oxidant may be subdivided between any two values chosen from 0.05 increments within the described range (endpoints inclusive). The concentration of any one reactant may be a specific value within its respective ranges. The mole ratio of the carbon containing compound/fluorine radioisotope/fluorinating catalyst/oxidant may be 1/(10 ¹² - 10^-9)/0.1/l.

[0054] The methods herein that include one-step C-H fluorination using ¹⁸F fluoride ion may be applied for labeling a drug to assess its biodistribution as well as pharmacokinetics and metabolic profile. The method may be applied for positron emission applications. The applications may include labeling a bioactive molecule to evaluate it as a potential radiotracer. Any compound made by a method herein or described herein may be used for any of these utilities. And methdos of using these compounds for these utilities are embodiments herein. FIG. 2 illustrates that this fluorination reaction allowed the efficient ¹⁸F labeling of benzylic C-H bonds in a wide range of substrates with radiochemical conversion rate (RCC) ranging from 20% to 68%. Bioactive compounds with a variety of functional groups may be the carbon containing compounds and may be fluorinated. Examples of bioactive compound functional groups that may be a moiety of a carbon containing compound herein include, without limitation, esters, amides, imides, ketones, alkynes, ethers, cyanides, heterocycles, carbamates, aryl or aliphatic halides. The labeling may be more efficient for substrates bearing electron- donating groups, presumably due to the electrophilic nature of the hydrogen- abstracting oxomanganese(V) intermediate. The method may be used to prepare ¹⁸F-labeled synthons (in addition to direct labeling for radiotracer evaluation). Referring to FIG. 2, dibenzosuberone (10), the chemical precursor of a series of tricyclic antidepressant drugs (TCAs) including amitriptyline and nortriptyline, was readily labeled with ¹⁸F in 50% RCC. The tolerance of reactive functional groups such as halogens and alkynes enables the rapid incorporation of ¹⁸F-labeled motifs into complex structures through well- established methods such as nucleophilic substitutions or "click" reactions (Marik, J.; Sutcliffe, J. L. Tetrahedron Lett. 2006, 47, 6681, which is incorporated herein by reference as if fully set forth). The ¹⁸F labeling reaction may be performed under air and without rigorous exclusion of water, greatly simplifying the protocol and facilitating scale-up.

[0055] Embodiments herein place ¹⁸F fluorine at previously inaccessible sites in biomolecules and drug candidates. The incorporation of ¹⁸F into biomolecules can allow direct imaging of metabolic activity and drug targets using the exquisite sensitivity of positron emission tomography (PET). An embodiment includes any carbon containing compound radiolabeled by a method herein. The products include modified drugs and imaging agents.

[0056] The methods of direct radioactive labeling herein may be compatible with typical "dry-down" procedures used in ¹⁸F chemistry. Embodiments of the method include "dry-down" procedures. Typically, the [¹⁸F]fluoride solution obtained from a cyclotron is a very dilute aqueous solution. For large-scale (100 milli Curies to several Curies) radio-synthesis, removing water and redissolving the [¹⁸F]fluoridein organic solution is generally required. As used herein, the term "dry- down procedure" refers to the procedure that includes iterative azeotropic evaporation of water from the very dilute [¹⁸F]fluoride solution derived from a cycltron to obtain anhydrous [¹⁸F] fluoride, which can be later dissolved in organic solution with a phase transfer catalyst. Generally, 3 cycles of azeotropic evaporation are required to obtain anhydrous [¹⁸F]fluoride. Each cycle includes adding 1 mL of anhydrous acetonitrile to the [¹⁸F]fluoride source containing an inorganic base; e.g., K2CO3, and heating the resulting mixture to dryness at 108 °C.

[0057] An embodiment includes a "dry- down free" method of direct radioactive labeling, wherein "dry- down" is not required but may be employed if desired. The term "dry- down free" procedure herein refers to the procedure, wherein the [¹⁸F] fluoride loaded onto the ion exchange cartridge can be directly extracted by the organic solution of the manganese catalyst due to the strong binding between the catalyst and [¹⁸F] fluoride, therefore bypassing the time- consuming azeotropic evaporation cycles ("dry- down" step). In a non-limiting example, [¹⁸F]Fluoride (6 mCi) deposited on an anion exchange cartridge (AEC) may be eluted using an organic solution of the catalyst; Mn(salen)OTs with 90% recovery of the radiolabel from the column and no erosion of the RCC in the subsequent fluorination reaction. FIG. 5 illustrates that "dry -down" procedure, in which ¹⁸F-labeled celestolide with 30% RCC was obtained from the subsequent reaction. This operationally simple, dry down-free protocol may be readily scalable for automated synthesis.

[0058] An embodiment includes the methods of fluorinating a compound with ¹⁸F herein, the compounds produced thereby, and downstream methods of using the compounds. Fluorinating a carbon containing compound with ¹⁸F may be achieved by a method of direct oxidative C-H fluorination herein. The method may include fluorinating the compound with ¹⁸F on site for delivery to the patient shortly after synthesis. The visualization of cellular processes by molecular imaging is a promising and non-invasive way to observe disease states and to improve the diagnoses (See Signore, A., Mather, S. J., Piaggio, G., Malviya, G., and Dierckx, R. A. Molecular imaging of inflammation/infection: nuclear medicine and optical imaging agents and methods. Chem. Rev. 2010, 110, 3112- 3145; and Pysz, M. A., Gambhir, S. S., and Willmann, J. K. Molecular imaging: current status and emerging strategies. Clin. Radiol. 2010, 65, 500-516, which are incorporated herein by reference as if fully set forth). Positron-emission tomography (PET) in particular, has emerged as a modality of choice because it yields well-resolved images with excellent sensitivity (See Wong, F. C, and Kim, E. E. A review of molecular imaging studies reaching the clinical stage. Eur. J. Radiol. 2009, 70, 205-211; Ametamey, S. M., Honer, M., and Schubiger, P. A. Molecular imaging with PET. Chem. Rev. 2008, 108, 1501-1516; and Chen, , and Conti, P. S. Target- specific delivery of pepti de-based probes for PET imaging. Adv. Drug Delivery Rev. 2010, 62, 1005-1022, which are incorporated herein by reference as if fully set forth). Among the seven positron-emitting isotopes, ¹⁸F has the advantages of a two-hour half and a β+ -emission at 635 keV (See Miller, P. W., Long, N. J., Vilar, R., and Gee, A. D. Synthesis of ^UC, ¹⁸F, ^O, and ⁱ³N radiolabels for positron emission tomography. Angew. Chem., Int. Ed. 2008, 47, 8998-9033; and Cai, L., Lu, S., and Pike, V. W. Chemistry with [¹⁸F] fluoride ion. Eur. J. Org. Chem. 2008, 2853-2873, which is incorporated herein by reference as if fully set forth). Imaging agents such as ¹⁸F-fluorodeoxyglucose (18F-FDG) have proved to be efficacious for imaging tissue and cells with high glucose metabolism (See Wadsak, W., and Mitterhauser, M. Basic principles of radiopharmaceuticals for PET/CT. Eur. J. Radiol. 2010, 73, 461-469, which is incorporated herein by reference as if fully set forth). A short-coming of current methods of ¹⁸F labeling is that the usual replacement of an oxygen functional group with fluorine changes the polarity of the detection molecule. The method of direct oxidative fluorination herein allows for the one- step replacement of a carbon-bound hydrogen, which has the advantages of using ¹⁸F from a fluoride ion source and creating a detection molecule that does not change the hydrogen bonding pattern of the starting compound.

[0059] An embodiment includes visualization by steps including 1) direct radioactive labeling of a carbon containing compound by a method herein to create an imaging agent, 2) administration of the imaging agent to a patient, and 3) positron emission tomography of the patient. The step of the direct radioactive labeling may include at least one of separation of the radioactively labeled compound by HPLC and purification of the separated radioactively labeled compound by a cartridge. The purified radioactively labeled compound may be added to a saline solution and administered to a subject in need thereof by injection. A dose of 200 μθί of ¹⁸F per mouse may be used in animal experiments. The skilled artisan would understand scaling of this amount.

[0060] Embodiments include methods of assessing biodistribution of a drug, pharmacokinetics, and analysis of metabolic profile by administering a composition including any ¹⁸F labeled compound herein to a study culture, tissue, organ, or organism. The organism may be an animal, mammalian, rat, mouse, dog, or human.

[0061] An embodiment includes a composition comprising the product of fluorinating a carbon containing compound having an sp3 C-H bond with radioactive fluorine. The product may be from the method as it is conducted on any target contained herein or an analog thereof. The composition may comprise one or more of fluoro-ibuprofen, fluoro-rasagiline, fluoro-nabumetone, fluoro- celestolide, fluoro-celecoxib analog, fluoro-papaverine, fluoro- protected enalaprilat, fluoro-protected fingolimod, fluoro-protected dopamine, or fluoro-N- Boc-cinacalcet, or pharmaceutically acceptable salts or solvates thereof. See FIG. 3 for examples. Pharmaceutically acceptable salts that may be included in embodiments herein can be found in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth (Eds.), VHCA, Verlag Helvetica Chimica Acta (Zurich, Switzerland) and WILEY- VCH (Weinheim, Federal Republic of Germany); ISBN: 3-906390-26-8, which is incorporated herein by reference as if fully set forth. A composition herein may comprise a pharmaceutically acceptable carrier, which may be selected from but is not limited to one or more in the following list: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, human serum albumin, buffer substances, phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, waxes, polyethylene glycol, starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, talc, magnesium carbonate, kaolin, non-ionic surfactants, edible oils, physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) and phosphate buffered saline (PBS). The ¹⁸F radioactively labeled drug molecules created by methods herein will have nearly the same steric size as the parent drug.

[0062] In an embodiment, the ¹⁸F-labeled drugs may be used as PET imaging agents. The ¹⁸F-drug molecules disclosed herein are inhibitors of certain biological targets, and may be used as PET imaging agents. Ibuprofen, nabumetone and celecoxib are inhibitors of COX-2, which is a major contributor to the inflammatory response and cancer progression. The ¹⁸F-ibuprofen, ¹⁸F- Nabumetone, ¹⁸F-celecoxib analog may be used as PET imaging agents. It has been reported that the ¹⁸F-labeled COX-2 inhibitors can be useful probe for early detection of cancer and for evaluation of the COX-2 status of premalignant and malignant tumors. Examples of compounds in compositions herein follow.

[0063] Rasagiline is a monoamine oxidase B (MAO B) inhibitor. The radiolabeled MAO B inhibitor provides an accurate probe for measuring brain MAO B, which will help early detection of multiple diseases including Alzheimer disease. An ^uC-labeled MAO B inhibitor, ^UC- L-deprenyl has been already widely used for PET-imaging. The ¹⁸F-rasagiline may also be used for PET-imaging.

[0064] Papaverine is a specific inhibitor of phosphodiesterase (PDE) 10A.

¹⁸F-papaverine could be useful for imaging PDE10A in the central nervous system (CNS). The ¹⁸F-papaverine may be used as a PET imaging agent.

[0065] Dopamine is an important neurotransmitter. ¹⁸F-labeled dopamines are potential tracers for the activity of Sympathetic nervous system. One ¹⁸F-labeled dopamine, 6-[¹⁸F]fluorodopamine has been successfully used as a functional imaging modality with high sensitivity for pheochromocytoma. The ¹⁸F-dopamine may also be used for PET imaging.

[0066] Enalapril is an angiotensin-converting-enzyme (ACE) inhibitor.

ACE is an important target for renal PET imaging. Several ¹⁸F-labeled ACE inhibitors have been successfully applied for renal PET imaging. The ¹⁸F- enalapril may also be applied for PET imaging.

[0067] Radiolabeled amino acids have wide applications in neuro- oncology, due to their low uptake in normal brain but high uptake in most brain tumors. FACPC and radiolabeled leucine and valine have found broad clinical applications. For example, L-[1-¹¹C] leucine has been used for determined human cerebral protein synthesis rates, and FACPC is useful in the detection of prostate carcinoma. The ¹⁸F-leucine, ¹⁸F-valine, and FACPC may be used as PET imaging agents. [0068] Flutamide is an androgen (AR) receptor, which is present in most advanced prostate cancers. ¹⁸F labeled flutamide derivatives have shown early success in quantitative molecular imaging of AR-positive prostate cancer. Thus, the ¹⁸F-flutamide may be useful as a PET imaging agent.

[0069] Amantadine is a dopaminergic agent and NMDA antagonist. PET imaging of NMDA in brain using radiolabeled NMDA receptors has provided useful information on the role of these receptors in various neurological disorders. The ¹⁸F-amantadine may be used for PET imaging applications.

[0070] In an embodiment, the ¹⁸F-drug molecules may be useful for pharmacokinetic studies. The ¹⁸F-drug molecules may be useful for optimizing methods of treatment.

[0071] Methods of studying pharmacokinetics, treatment, optimizing treatment, assessing biodistribution, or analyzing metabolic profile with one or more ¹⁸F compounds herein may include administering the ¹⁸F compound to a subject. Further representative examples of ¹⁸F compounds that may be in a composition herein or a method herein follow. Indications of disease states, treatments and dosing are also given.

[0072] Referring to FIG. 3, the ¹⁸F-drug molecules may be the ¹⁸F fluoro- ibuprofen. Embodiments also include the methods of using or making a radiolabeled compound described herein with respect to making ¹⁸F fluoro- ibuprofen. Ibuprofen is a widely used NSAID analgesic agent. It is known to cross the blood brain barrier and has shown promising results in reducing inflammation associated with Alzheimer's disease. Any of the four stereoisomers of 2-(4-(2-methyl-l-fluoro-propyl)phenyl)propanoic acid or any combination thereof are embodiments herein (see structure below). All four of these stereoisomers may be prepared by basic hydrolysis of the precursor fluoro-ibuprofen methyl ester. Enzyme inhibition studies have shown that the fluorinated derivatives have equal or greater inhibition of prostaglandin synthases (COX 1 and COX 2) than the parent drug. The ¹⁸F fluoro-ibuprofen may also bind to these targets. Thus, ¹⁸F fluoro-ibuprofen would be expected to bind to and detect the location of COX enzymes in the brain. This property could be used to detect areas of inflammation in the brain associated with disorders including but not limited to Alzheimer's disease. Methods of using an ¹⁸F fluorinated compound herein include administering one or more of ¹⁸F fluoro- ibuprofen or fluoro-ibuprofen methyl ester.

Racemic ibuprophen (RS)-2-(4-(2-methyl Fluoro-ibuprophen two racemic pairs propyl)phenyl) propanoic acid

[0073] In an embodiment, ^1SF fluoro-ibuprofen maj^ be used for studying pharmacokinetics, optimizing methods of treatment of a subject in need thereof, assessing biodistribution, analyzing the metabolic profile of ^1SF fluoro-ibuprofen. The ^1SF fluoro-ibuprofen may be administered to the subject. The subject may suffer from or be at risk from suffering from any disease or condition in which inflammation is the root symptom or cause of secondary injury. The dose may be but is not limited to any value greater than zero in the range from zero to 3200 mg, or in a sub-range with endpoints chosen from any two values evenly divisible by two in the zero to 3200 mg range. The subject may be a dysmenorrhea subject. The adult dose for a dysmenorrhea patient may be 200 to 400 mg orally every 4 to 6 hours as needed. The subject may be an osteoarthritis subject. When used for treatment, the fluoro-ibuprofen dose may be as follows. The adult dose for an osteoarthritis subject may be initially 400 to 800 mg orally every 6 to 8 hours. It may then be increased to a daily dose of 3200 mg based on subject response and tolerance. The subject may be a rheumatoid arthritis patient. The adult dose for a rheumatoid arthritis may initially be 400 to 800 mg orally every 6 to 8 hours. It may then be increased to a daily dose of 3200 mg based on subject response and tolerance. The subject may be a headache subject. The adult dose for a headache subject may be 100 to 1000 mg. The timing of doses could be used to detect areas of inflammation in the brain associated with disorders including but not limited to Alzheimer's disease. Methods of using an 1⁸F fluorinated compound herein include administering one or more of ¹⁸F fluoro-ibuprofen or fluoro-ibuprofen methyl ester.

[0073] In an embodiment, ¹⁸F fluoro-ibuprofen may be used for studying pharmacokinetics, optimizing methods of treatment of a subject in need thereof, assessing biodistribution, analyzing the metabolic profile of ¹⁸F fluoro-ibuprofen. The ¹⁸F fluoro-ibuprofen may be administered to the subject. The subject may suffer from or be at risk from suffering from any disease or condition in which inflammation is the root symptom or cause of secondary injury. The dose may be but is not limited to any value greater than zero in the range from zero to 3200 mg, or in a sub-range with endpoints chosen from any two values evenly divisible by two in the zero to 3200 mg range. The subject may be a dysmenorrhea subject. The adult dose for a dysmenorrhea patient may be 200 to 400 mg orally every 4 to 6 hours as needed. The subject may be an osteoarthritis subject. When used for treatment, the fluoro-ibuprofen dose may be as follows. The adult dose for an osteoarthritis subject may be initially 400 to 800 mg orally every 6 to 8 hours. It may then be increased to a daily dose of 3200 mg based on subject response and tolerance. The subject may be a rheumatoid arthritis patient. The adult dose for a rheumatoid arthritis may initially be 400 to 800 mg orally every 6 to 8 hours. It may then be increased to a daily dose of 3200 mg based on subject response and tolerance. The subject may be a headache subject. The adult dose for a headache subject may be 100 to 1000 mg. The timing of doses

-20- may be every three hours. The subject may suffer from inflammation, and the dose may be 200-800 mg every 4-6 hours. A method may include administering the fluoro-ibuprofen to a headache subject to prevent electroconvulsive therapy (ECT)-induced headache. The adult dose to prevent electroconvulsive therapy (ECT)-induced headache may be 600 mg orally. The dose may be given 90 minutes prior to the initial ECT session. The subject may be suffering from pain. The adult dose for pain may be 200 to 400 mg orally every 4 to 6 hours as needed for moderate pain. The dose may be 400 to 800 mg intravenously over 30 minutes every 6 hours as needed. The subject may be suffering from a fever. The adult dose for a fever may be 200 to 400 mg orally every 4 to 6 hours as needed. The adult dose for fever may initially be 400 mg intravenously over 30 minutes, and then 400 mg every 4 to 6 hours or 100 to 200 mg every 4 hours as needed. The pediatric dose for fever, for a child 6 months to 12 years, may be 5 mg/kg/dose for a temperature less than 102.5°F (39.2°C) orally every 6 to 8 hours as needed. The pediatric dose, for a child 6 months to 12 years, may be 10 mg/kg/dose for temperature greater than or equal to 102.5°F (39.2 °C) orally every 6 to 8 hours as needed. The pediatric dose as an analgesic, antipyretic may be: 6 months to 11 years: 7.5 mg/kg/dose every 6 to 8 hours. The pediatric dose for pain in infants and children may be: 4 to 10 mg/kg orally every 6 to 8 hours as needed. The subject may be a pediatric rheumatoid arthritis (6 months to 12 years) subject. The dose for pediatric rheumatoid arthritis may be 30 to 40 mg/kg/day in 3 to 4 divided doses. The treatment may include starting at the lower end of dosing range and titrate; patients with milder disease may be treated with 20 mg/kg/day. The subject may be a pediatric cystic fibrosis patient. The dose for pediatric cystic fibrosis may be as follows: Chronic (greater than 4 years) twice daily dosing adjusted to maintain serum concentration of 50 to 100 mcg/mL. The subject may be a pediatric ductus arteriosus victim. The fluoroibuprofen may be modified to be fluoro-ibuprofen lysine. The dose may be as follows: Gestational age 32 weeks or less, birth weight: 500 to 1500 g - an initial dose: 10 mg/kg, followed by two doses of 5 mg/kg after 24 and 48 hours. Birth weight may be used to calculate all doses. The method may include

-21- studying the pharmacokinetics of a precursor of a ¹⁸F fluoro-ibuprofen in a subject. The ¹⁸F precursor of the fluoro-ibuprofen may be administered to the subject with subsequent conversion of the precursor to ¹⁸F fluoro-ibuprofen in vivo. The methods herein may include studying the pharmacokinetics of ¹⁸F fluoro-ibuprofen or ¹⁸F fluoro-methyl-ester ibuprofen by administering the same to a subject in need thereof. The doses and indications may be as set forth for fluoro-ibuprofen and may be adjusted based on the pharmacokinetics study.

[0074] Still referring to FIG. 3, embodiments include studying the pharmacokinetics of, optimizing methods of treatment with, assessing biodistribution of and analyzing the metabolic profile of ¹⁸F fluoro-rasagiline. Rasagiline is a monoamine oxidase-B (MAO-B) inhibitor, and is used to treat the symptoms of Parkinson's disease - sometimes in combination with levodopa. An embodiment includes compositions comprising ¹⁸F fluoro-rasagiline in combination with levodopa. The methods may include administering ¹⁸F- fluoro- rasagiline to a subject in need thereof. The subject may be a Parkinson's disease subject. The dose may be but is not limited to any value greater than zero in the range from zero to 10 mg, or in a sub-range with endpoints chosen from any two values evenly divisible by two in the zero to 10 mg range. The dose may be 0.2-2 mg daily. In an embodiment, the method includes monotherapy with rasagiline at 1 mg orally once daily. In an embodiment, the method includes adjunctive therapy (in combination with levodopa) with rasagailine at 0.5 mg orally once daily. The adjunctive therapy dose rasagiline of may be increased to 1 mg orally daily. The therapeutic dose may be adjusted based on the results of the pharmacokinetics study.

[0075] Still referring to FIG. 3, an embodiment includes studying the pharmacokinetics of, optimizing methods of treatment with, assessing biodistribution of, and analyzing the metabolic profile of ¹⁸F fluoro-nabumetone. Nabumetone reduces hormones that cause inflammation and pain in the body. One use of nabumetone is to treat pain or inflammation caused by arthritis. The dose may be 200-2000 mg/day for inflammation. A single dose may be but is not limited to any value greater than zero in the range from zero to 1000 mg, or in a

-22- sub-range with endpoints chosen from any two values evenly divisible by two in the zero to 1000 mg range. The subject may be suffering from pain. The subject may have arthritis, osteoarthritis, or rheumatoid arthritis. The initial dose when treating osteoarthritis may be 1000 mg once a day at bedtime. The maintenance dose when treating osteoarthritis may be 500 to 2000 mg orally in 1 to 2 divided doses. The initial dose when treating rheumatoid arthritis may be 1000 mg once a day at bedtime. The maintenance dose when treating rheumatoid arthritis may be 1500 to 2000 mg orally in 1 to 2 divided doses. The treatment dose may be adjusted based on the results of the pharmacokinetics study.

[0076] Still referring to FIG. 3, an embodiment includes studying the pharmacokinetics of, optimizing methods of treatment with, assessing biodistribution of, and analyzing the metabolic profile of ¹⁸F- fluoro-celestolide.

[0077] Still referring to FIG. 3, an embodiment includes studying the pharmacokinetics of, optimizing methods of treatment with, assessing biodistribution of and analyzing the metabolic profile of ¹⁸F-fluoro-celecoxib analog. Celecoxib is used to treat pain or inflammation caused by many conditions, including arthritis, ankylosing spondylitis, and menstrual pain. Celecoxib is also used in the treatment of hereditary polyps in the colon. An embodiment includes a method of treatment comprising administering ¹⁸F-fluoro- celecoxib analog to a subject in need thereof. The dose may be 200-2000 mg/day for inflammation. A single dose may be but is not limited to any value greater than zero in the range from zero to 400 mg, or in a sub-range with endpoints chosen from any two values evenly divisible by two in the zero to 400 mg range. The subject may be suffering from pain. The subject may by a dysmenorrhea subject, and the dose may be 400 mg initially, followed by 200 mg if needed on the first day. Then, 200 mg twice daily as needed. The subject may be a osteoarthritis subject, and the dose may be 200 mg orally once daily or 100 mg orally twice daily. The subject may be a rheumatoid arthritis subject and the dose may be 100 to 200 mg orally twice daily for subjects at greater than 25 kg. The juvenile (2 years and older) dose for rheumatoid arthritis may be 50 mg orally twice daily for subjects at 10 to less than or equal to 25 kg, and 100 mg

-23- orally twice daily for subjects greater than 25 kg. The subject may suffer from familial adenomatous polyposis, and the dose may be 400 mg orally twice daily with food. The subject may suffer from ankylosing spondylitis, and the dose may be 200 mg orally once daily or 100 mg orally twice daily. If after 6 weeks of therapy no results are observed, a trial dose of 400 mg orally daily may be delivered. The treatment dose may be adjusted based on the pharmacokinetics study.

[0078] Still referring to FIG. 3, an embodiment includes studying the pharmacokinetics of, optimizing methods of treatment with, assessing biodistribution of and analyzing the metabolic profile of ¹⁸F- fluoro-papaverine. Papaverine is a vasodilator that relaxes smooth muscles in blood vessels, causing dilation. This lowers blood pressure and allows blood to flow more easily through veins and arteries. Papaverine is used to treat many conditions that cause spasm of smooth muscle. This includes chest pain, circulation problems, heart attack, or disorders of the stomach or gallbladder. The dose of fluoro-papaverine may be similar to that of papaverine for the various indications. The dose may be 50 to 500 mg 3 to 5 times daily for acute myocardial infarction (coronary occlusion), angina pectoris, peripheral andpulmonary embolism, or peripheral vascular disease. The dose may be adjusted based on the pharmacokinetics study.

[0079] Still referring to FIG. 3, an embodiment includes studying the pharmacokinetics of, optimizing methods of treatment with, assessing biodistribution of and analyzing the metabolic profile of ¹⁸F-fluoro-protected enalaprilat. Enalaprilat is an angiotensin- converting enzyme (ACE) inhibitor. The dose of fluoro-protected enalaprilat may be similar to that of enalaprilat. The dose may be 1-20 mg/day ACE inhibitor for control of blood pressure. The dose may be adjusted based on the results of the pharmacokinetics study.

[0080] Still referring to FIG. 3, an embodiment includes studying the pharmacokinetics of, optimizing methods of treatment with, assessing biodistribution of and analyzing the metabolic profile of ¹⁸F- fluoro-protected fingolimod. Fingolimod is an immunosuppressant that traps immune cells in lymph nodes, preventing their travel to the central nervous system. Fingolimod

-24- is used to treat relapsing multiple sclerosis (MS) in adults. A single dose may be but is not limited to any value greater than zero in the range from zero to 0.5 mg. The subject may suffer from multiple sclerosis, and the dosage may be 0.5 mg orally once a day. The subject may be a patient. The dose may be 0.1-1.0 mg/day for the treatment of patients with relapsing forms of multiple sclerosis (MS). The treatment dose may be modified in accordance with the pharmacokinetics study.

[0081] Still referring to FIG. 3, an embodiment includes studying the pharmacokinetics of, optimizing methods of treatment with, assessing biodistribution of and analyzing the metabolic profile of ¹⁸F-fluoro-protected dopamine. Dopamine improves the pumping strength of the heart and improves blood flow to the kidneys. Dopamine injection (Intropin) is used to treat certain conditions, including low pressure that may occur from shock, which may be caused by heart attack, trauma, surgery, heart failure, kidney failure, and other serious medical conditions. The dose may be 200 - 500 mg orally twice a day, up to 2000 to 8000 mg/day in several doses for Parkinson's disease, 10-100 mg/day for restless leg syndrome. A single dose may be but is not limited to any value greater than zero in the range from zero to 50 mcg/kg/min, or in a sub-range with endpoints chosen from any two values evenly divisible by 5 in the zero to 50 mcg/kg/min range. The subject may suffer from nonobstructive oliguria, and the dose may be 1 to 5 mcg/kg/min by continuous IV infusion initially, and then titrated to desired response. The subject may suffer from shock, and the dose may be 1 to 5 mcg/kg/min by continuous IV infusion initially, and then titrated to a desired reponse. The subject may be pediatric and suffer from shock, and the dose may be 1 to 20 mcg/kg/min by continuous IV infusion initially, and then titrated to a desired response. The treatment dose may be adjusted based on the pharmacokinetics study.

[0082] Still referring to FIG. 3, an embodiment includes studying the pharmacokinetics of, optimizing methods of treatment with, assessing biodistribution of and analyzing the metabolic profile of ¹⁸F- fluoro-N-Boc- cinacalcet. Cinacalcet decreases levels of parathyroid hormone (PTH), calcium, and phosphorous in the body, and is used to treat hyperparathyroidism

-25- (overactive functioning of the parathyroid glands) in people who are on long-term dialysis for kidney disease. Cinacalcet is also used to lower calcium levels in people with cancer of the parathyroid gland. The dose may be 20-500 mg/day for primary hyperparathyroidism, secondary hyperparathyroidism, or hypercalcemia of malignancy. A single dose may be but is not limited to any value greater than zero in the range from zero to 360 mg, or in a sub-range with endpoints chosen from any two values evenly divisible by 2 in the zero to 180 mg range. The subject may suffer from secondary hyperparathyroidism, and the dose may initially be 30 mg orally once a day (and titrated every 2 to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg orally once daily). The maintenance dose may be 0 to 180 mg orally once a day. The subject may suffer from hypercalcemia of malignancy, and the dose may initially be 30 mg orally twice a day (and titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg 3 or 4 times daily). The maintenance dose may be 60 mg to 360 mg orally per day. The subject may suffer from primary hyperparathyroidism, and the dose may initially be 0 mg orally twice a day (and titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg 3 or 4 times daily). The maintenance dose may be 60 mg to 360 mg orally per day. The dose may be modified based on the pharmacokinetics study.

[0083] Methods of preparing a PET scan probe and PET scanning described herein may include preparing either ¹⁸F probe or a precursor thereof and administering the same to a PET scan patient. The ¹⁸F probe may be ¹⁸F fluoro- ibuprofen. The precursor of ¹⁸F fluoro-ibuprofen may be ¹⁸F fluoro-ibuprofen methyl ester. The method may include PET scan of any area of the patient. The method may include a PET scan of an Alzheimer's disease patient, and the area of the patient scanned may be the patient's brain.

[0084] Embodiments

[0085] The following list includes particular embodiments of the present invention. The list, however, is not limiting and does not exclude alternate embodiments, as would be appreciated by one of ordinary skill in the art.

-26- 1. A method of direct radioactive labeling of a carbon containing compound having an sp3 C-H bond comprising: combining the carbon containing compound, a fluorine radioisotope, a fluorinating catalyst, a solvent and an oxidant, wherein the fluorinating catalyst is a manganese salen complex comprising a weakly coordinated anion as an axial ligand; a manganese porphyrin complex comprising a weakly coordinated anion as an axial ligand, or any other manganese catalyst described or incorporated herein.

2. The method of embodiment 1, wherein the weakly coordinated anion is selected from the group consisting of: trifluoromethanesulfonate(OTf), toluenesulpfonate (OTs), perchlorate (CIO4), tetrafluoroborate (BF4), hexafluorophosphate (PF₆), BARF ([B[3,5-(CF3)2C₆H₃] 4]), hexafluoroantimonate(V) (SbFe), methanesulfonate (OMs), and 4- nitrobenzenesulfonate.

3. The method of any one of embodiments 1 or 2, wherein the fluorinating catalyst is a manganese porphyrin complex.

4. The method of embodiment 3, wherein the manganese porphyrin complex includes one or more meso-substituents in the porphyrin ring.

5. The method of embodiment 4, wherein the one or more meso- substituents is selected from the group consisting of: mesityl, phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, tetramesityl, tetraphenyl, pentafluorophenyl, tetradifluorophenyl, tetradichlorophenyl, tetrakis-(l,3-dimethylimidazolium-2-yl), and

tetrakis(N-methylpyridinium-2-yl), and tetrakis(N-methylpyridinium-4-yl).

6. The method of any one or more of the preceding embodiments, wherein the fluorinating catalyst is a manganese porphyrin complex selected from the group consisting of: Mn(TMP)OTs, Mn(TPP)OTs, Mn(TDFPP)OTs,

-27- Mn(TDClPP)OTs, Mn(TPPFPP)OTs, Mn(TDImP)OTs, Mn(2-PyP)OTs, and Mn(4-PyP)OTs.

7. The method of embodiment 1, wherein the fluorinating catalyst is the manganese salen complex.

8. The method of embodiment 1, wherein the fluorinating catalyst is the manganese salen complex selected from the group consisting of: Mn(salen)OTf, Mn(salen)OTs and Mn(salen)ClO₄.

9. The method of any one or more of the preceding embodiments, wherein the fluorine radioisotope is ¹⁸F.

10. The method of embodiment 9, wherein the ¹⁸F is an aqueous ¹⁸F fluoride.

11. The method of claim any one or more of the preceding embodiments, the wherein the oxidant is selected from the group consisting of meta- chloroperoxybenzoic acid (mCPBA), idosylbenzene, peroxyacid, alkyl peroxide, peroxy sulfate(oxone), peroxycarbonate, peroxyborate, iodosyl mesitylene, pentafluoro-iodosylbenzene, benzene difluoroiodinane [phenyl-IF2], diacetoxyiodobenzene, 2-iodosylbenzoic acid, peroxyacetic acid, peroxyphthalic acid, peroxytungstic acid.

12. The method of any one or more of the preceding embodiments, wherein the solvent is acetone, acetonitrile or a combination thereof.

13. The method of any one or more of the preceding embodiments, wherein the carbon containing compound is selected from the group consisting of: inhibitors of cyclooxygenase (COX), inhibitors of monoamine oxidase B (MAO-B), inhibitors of phosphodiesterase 10A (PDEIOA), inhibitors of

-28- angiotensin- converting enzyme (ACE), bio-messenger molecules, the neurotransmitter dopamine, fingolimod, Leucine-derivatives, Valine- derivatives, Leucine dipeptide, Boc-Valine-Luecine methyl ester, tyrosine derivative, pregabalin LYRICA^®, Boc-Amantidine, flutamide, aminocyclopentane carhoxylic acid, ibuprofen, ibuprofen methyl ester, rasagiline, nabumetone, celecoxib analog, papaverine, protected enalaprilat, protected fingolimod, protected dopamine, N-Boc-cinacalcet, JNJ41510417, 5- OH-FPPAT, FEP, Acl703. BMIPP, HAR, flutemetamol, MK-9470, FACPC, CURB, MFES, FES, 2-ME, PHNO, PHNO, fallypride, DMFP, 5-OH-FPPAT, 5- OH-DPAT, NPA, NNC112, SCH, FDA, MNPA, MC113, SA4503, SA6298, BMS- 747158-01, PBR28, PBR06, FMPEP, MePPEP, FBzBMS, FBFPA, FEPPA, telmisartan, tacrine, desloratadine, etodolac, cinacalcet, tanshinone IIA, indomethacin, trimethoprim, masoprocol, dubutamine, duloxetine, ondansetron, benzbromarone, simple alkanes, neopentane, toluene, cyclohexane, norcarne, simple hydrocarbons, trans-decalin, 5a-cholestane, sclarolide;, 1, 3, 5(10)-estratrien-17-one, (lR,4aS, 8aS)-octahydro-5,5,8a- trimethyl-l-(3-oxobutyl)-naphtalenone, (1R, 4S, 6S, 10S)-4, 12, 12-trimethyl- tricyclo[8.2.0.04,6]dodecan-9-one, levomethorphan, lupine, 20-methyl- 5alpha(H)-pregnane, isolongifolanone, caryophyllene acetate, N-acetyl- gabapentin methyl ester, acetyl-amantidine, phthalimido-amantadine, methyloctanoate, other saturated fatty acid esters, N- acetyl- Lyrica methyl ester, artemisinin, adapalene, finasteride, N-acetyl-methylphenidate, mecamylamine, N-acetyl-mecamylamine, N-acetyl-memantine, phthalimidi- memantine, N- acetyl- Enanapril precursor methyl ester, progesterone, artemisinin, adapalene, dopamine derivative, pregabalin, cholestane, finasteride, methylphenidate derivative, mecamylamine, gabapentin, memantine derivative, gabapentin, isoleucine derivatives, progesterone, tramadol, and (1R, 4aS, 8aS)-5, 5, 8a-trimethyl-l-(3- oxobutyl)octahy dronaphthalen- 2( 1 H) - one .

-29- 14. The method of embodiment 13, wherein the carbon containing compound is a monofluoro containing compound.

15. The method of any one or more of embodiments 1 -12, wherein the carbon containing compound is a monofluoro containing compound having an sp3 C-H bond, preferrably the sp3 C-H bond is to a carbon that is also bound to the fluoro moiety.

16. The method of any one or more of the preceding embodiments, wherein after combining the carbon containing compound is at a concentration from 0.1 mol/L to 0.6 mol/L, the fluorine radioisotope is at a concentration from 20 μϋί/ηιΐ to 5Ci/ml, the fluorinating catalyst is at a concentration from 0.01 mol/L to 0.03 mol/L, and the oxidant is added in a concentration from 0.05 mol/L to 0.6 mol L.

17. The method of embodiment 16, wherein the volume of the solvent is 0.1 mL to 1 mL.

18. The method of any one or more of the preceding embodiments, wherein the step of combining includes mixing the carbon containing compound and the fluorinated catalyst to form a first mixture, mixing the fluorine radioisotope and the solvent to form a second mixture, mixing the first mixture and the second mixture to form a third mixture, and adding the antioxidant to the third mixture.

19. The method of any one or more of the embodiments 1 - 17, wherein step of combining includes mixing the fluorine radioisotope and the solvent to form a first mixture, adding the first mixture to the fluorinating catalyst to form a second mixture, adding the second mixture to the carbon containing compound to form a third mixture, and adding the antioxidant to the third mixture.

-30- 20. The method of any one of embodiments 18 or 19 wherein prior to the combining the aqueous ¹⁸F fluoride is purified in a cartridge to form a washed 1⁸F-fluoride solution.

21. The method of any one or more of the preceding embodiments further comprising allowing the carbon containing compound, the fluorine radioisotope, the fluorinating catalyst, the solvent and the oxidant to react for 10 minutes to 30 minutes.

22. The method of any one or more of the preceding embodiments further comprising maintaining the carbon containing compound, the fluorine radioisotope, the fluorinating catalyst, the solvent and the oxidant at a temperature of 20°C to 70°C.

23. The method of any one or more of the preceding embodiments, wherein the temperature is 50°C.

24. The method of any one or more of the preceding embodiments, wherein the fluorinating agent includes ¹⁸F and a product produced by the method includes ¹⁸F.

25. The method of any one or more of the preceding embodiments, wherein a radio-labeled product includes at least one compound selected from the group consisting of:

Me

Compound 2

Compound 3

Compound 4

-31- C

ompound 14

Compound 15

Compound 16

Compound 17

-32- Compound 18

F

Compound 19

Compound 20

Compound 21

Compound 22

-Tf

Diastereomer 23a CQ F

Diastereo

Compoun

Compound

Compound

Compound

-33- C

ompound 32

Compound 33

Compound 34

Compound 35 MeO

-34- Compound 36

Compound 37 MeO

Compound 38

Compound 39

Compound

Compound

Compound

-35- Compound 43

Compound 44 '

Compound 45

Compound 46

Compound 47

Compound 48

Compound 49

-36- Compound

Compound 51

Compound 52

-37- Compound 57

Compound 58

Compound 59

Compound 60

Compound 61

wherein the F in compounds 2 - 22, the F in diastereomers 23a - 23b, the F in compounds 24 - 54, and at least one F in compounds 54 - 58 is ¹⁸F.

26. The method of any one or more of embodiments 1 - 24, wherein a radio-labeled product includes the ¹⁸F labeled compound of claim 13.

27. The method of any one or more of the preceding embodiments, wherein a radio labeled product includes monofluoro derivative of the carbon containing compound.

-38- 28. The method of any one or more of the preceding embodiments further comprising obtaining an aqueous [¹⁸F] fluoride solution from a cyclotron, loading the aqueous [¹⁸F]fluoride solution onto an ion exchange cartridge, and releasing the [¹⁸F] fluoride from the ion exchange cartridge with a solution of the fluorinating catalyst.

29. The method of claim 28, further comprising rinsing the ion exchange cartridge prior to releasing.

30. The method of claim 29, wherein the rinsing is accomplished with the anyhydrous acetonitrile.

31. The method of claim 28, wherein the ion exchange cartridge is an anion exchange cartridge.

32. A composition comprising the product of the method of any one of embodiments 1— 31.

33. A method of visualization comprising: fluorinating a carbon containing compound having an sp3 C-H bond by the method of any one of embodiments 1— 31 where the fluorinating agent includes ¹⁸F and a product produced by the method includes ¹⁸F to create an imaging agent; administering the imaging agent to a patient; and performing positron emission tomography on the patient.

34. A composition comprising at least two or more of a carbon containing compound, a fluorine radioisotope, a fluorinating catalyst and an oxidant.

35. A composition comprising a fluorinating catalyst that is manganese complex comprisisng a weakly coordinated anion as an axial ligand.

-39- 36. The composition of embodimemt 35, wherein the manganese complex is a manganese porphyrin complex or a manganese salen complex.

37. The composition of any one or more of embodiment 35 - 36, wherein the weakly coordinated anion is selected from the group consisting of: trifluoromethanesulfonate (OTf), toluenesulpfonate (OTs), perchlorate (CIO4), tetrafluoroborate (BF₄), hexafluorophosphate (PF₆), BARF ([B[3,5- (CF3)2C6H3]₄]), hexafluorophosphate (PFe), hexafluoroantimonate(V) (SbFe), methanesulfonate (OMs), and 4-nitrobenzenesulfonate.

38. The composition of any one or more of embodiments 35 - 37, wherein the manganese complex is a manganese porphyrin complex comprising one or more meso-substituents in the porphyrin ring, wherein the one or more meso- substituents is selected from the group consisting of: mesityl, phenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, tetramesityl, tetraphenyl, pentafluorophenyl, tetradifluorophenyl, tetradichlorophenyl, tetrakis-(l,3-dimethylimidazolium-2-yl), and

tetrakis(N-methylpyridinium-2-yl), and tetrakis(N-methylpyridinium-4-yl).

39. The composition of any one or more of embodiments 35 - 38, wherein the manganese complex is selected from the group consisting of: Mn(TMP)OTs, Mn(TPP)OTs, Mn(TDFPP)OTs, Mn(TDClPP)OTs, Mn(TPPFPP)OTs, Mn(TDImP)OTs, Mn(2-PyP)OTs, and Mn(4-PyP)OTs.

40. The composition of any one or more of embodiments 35 - 37, wherein the manganese complex is a manganese salen complex.

41. The composition of any one or more of embodiments 35 - 36 and 40, wherein the manganese complex is selected from the group consisting of: Mn(salen)OTf, Mn(salen)OTs and Mn(salen)ClO₄.

-40- 42. A composition comprising at least two or more of a carbon containing compound having an sp3 C-H bond, a fluorine radioisotope, a fluorinating catalyst, a solvent, and an oxidant.

43. The composition of embodiment 42, wherein the carbon containing compound is selected from the group consisting of inhibitors of cyclooxygenase (COX), inhibitors of monoamine oxidase B (MAO-B), inhibitors of phosphodiesterase 10A (PDEIOA), inhibitors of angiotensin-converting enzyme (ACE), bio-messenger molecules, the neurotransmitter dopamine, fingolimod, Leucine-derivatives, Valine -derivatives, Leucine dipeptide, Boc-Valine-Luecine methyl ester, tyrosine derivative, pregabalin LYRICA^®, Boc-Amantidine, flutamide, aminocyclopentane carboxylic acid, ibuprofen, ibuprofen methyl ester, rasagiline, nabumetone, celecoxib analog, papaverine, protected enalaprilat, protected fingolimod, protected dopamine, N-Boc-cinacalcet, JNJ41510417, 5-OH- FPPAT, FEP, Acl703. BMIPP, HAR, flutemetamol, MK-9470, FACPC, CURB, MFES, FES, 2-ME, PHNO, PHNO, fallypride, DMFP, 5-OH-FPPAT, 5-OH- DPAT, NPA, NNC112, SCH, FDA, MNP A, MC113, SA4503, SA6298, BMS- 747158-01, PBR28, PBR06, FMPEP, MePPEP, FBzBMS, FBFPA, FEPPA, telmisartan, tacrine, desloratadine, etodolac, cinacalcet, tanshinone IIA, indomethacin, trimethoprim, masoprocol, dubutamine, duloxetine, ondansetron, benzbromarone, simple alkanes, neopentane, toluene, cyclohexane, norcarne, simple hydrocarbons, neopentane; toluene; cyclohexane; norcarane; t rans- decalin; 5a-cholestane; sclareolide; 1, 3, 5(10)-estratrien-17-one; (lR,4aS, 8aS)-octahydro- 5,5,8a-trimethyl-l-(3-oxobutyl)-naphtalenone; (1R, 4S, 6S, 10S)-4, 12, 12- trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one; levomethorphan; lupine; 20-methyl- 5alpha(H)-pregnane; isolongifolanone; caryophyllene acetate; N-acetyl- gabapentin methyl ester; acetyl- amanti dine; phthalimido-amantadine; methyloctanoate; saturated fatty acid esters; N-acetyl-Lyrica methyl ester; artemisinin, adapalene; finasteride; N-acetyl-methylphenidate; mecamylamine; N-acetyl-mecamylamine; N-acetyl-memantine; phthalimidi-memantine; N-acetyl- enanapril precursor methyl ester; progesterone; artemisinin; adapalene;

-41- dopamine derivative; pregabalin; cholestane; finasteride; methylphenidate derivative; mecamylamine; gabapentin; memantine derivative; gabapentin; rimantadine derivative; isoleucine derivative; leucine derivative; valine derivative; pregesterone; tramadol; enalapril precursor; (1R, 4aS, 8aS)-5, 5, 8a- trimethyl- 1 - (3- oxobutyl)octahy dronaphthalen- 2 (1 H)- one ; phenylalanine ; donepezil precursor; amphetamine; δ-tocopherol form of vitamin E; tyrosine; melatonin; tryptophan; estrone acetate; progesterone; dopamine; homophenylalanine; DOPA; ibuprofen methyl ester; buspirone; eticyclidine; memantine; amantadine; lubiprostone; penridopril; fosinopril; N-Phth amantadine; N-Phth Memantine; 2-adamantanone; rimantadine analogue; adapalene precursor; perindopril precursor; protected gabapentin; methyl octanoate; methyl nonanate; methyl hexanoate; cyclohexyl acetate; and cyclohexane carboxylic acid methyl ester; or an analog of any one of the foregoing.

44. The composition of any one or more of embodiments 42 - 43, wherein the fluorine radioisotope is ¹⁸F.

45. The composition of embodiment 42, wherein the ¹⁸F is an aquesous ¹⁸F-fluoride.

46. The composition of any one or more of the embodiments 42 - 45, wherein the fluorinating catalyst is selected from the group consisting of: Mn(TMP)OTs, Mn(TPP)OTs, Mn(TDFPP)OTs, Mn(TDClPP)OTs, Mn(TPPFPP)OTs, Mn(TDImP)OTs, Mn(2-PyP)OTs, and Mn(4-PyP)OTs.

47. The composition of any one or more of the embodiments 42 - 45, wherein the fluorinating catalyst is selected from the group consisting of: Mn(salen)OTf, Mn(salen)OTs and Mn(salen)C10₄.

48. The composition of any one or more of the embodiments 42 - 47, wherein the oxidant is selected from the group consisting of meta-

-42- chloroperoxybenzoic acid (mCPBA), idosylbenzene, peroxyacid, alkyl peroxide, peroxy sulfate(oxone), peroxycarbonate, peroxyborate, iodosyl mesitylene, pentafluoro-iodosylbenzene, benzene difluoroiodinane [phenyl-IF2], diacetoxyiodobenzene, 2-iodosylbenzoic acid, peroxyacetic acid, peroxyphthalic acid, and peroxytungstic acid.

49. A kit comprising one or more container, wherein each container includes a composition comprising at least one reactant for a radioactive labeling selected from the group consisting of a carbon containing compound, a fluorine radioisotope, a fluorinating catalyst, and an oxidant, wherein each composition includes at least one fewer substance than required to make a fluorination reaction proceed.

50. The kit of embodiment 49, further comprising a container having a solvent.

51. The kit of embodiment 49, wherein at least one of the containers includes a solvent.

52. The kit of any one or more of embodiments 49 - 51, wherein the one or more containers in combination include all the substances required to make the fluorination reaction proceed.

53. The kit of any one or more of embodiments 49 - 52, further comprising instructions for mixing the reactants from the at least one container.

54. A composition comprising a product of a method of direct oxidative C-H fluorination of a carbon containing compound having an sp3 C-H bond comprising combining the carbon containing compound, a fluorine radioisotope, a fluorinating catalyst, and an oxidant.

-43- 55. The composition of embodiment 54, wherein the carbon containing compound is selected from the group consisting of: inhibitors of cyclooxygenase (COX), inhibitors of monoamine oxidase B (MAO-B), inhibitors of phosphodiesterase 10A (PDEIOA), inhibitors of angiotensin-converting enzyme (ACE), bio-messenger molecules, the neurotransmitter dopamine, fingolimod, Leucine-derivatives, Valine -derivatives, Leucine dipeptide, Boc-Valine-Luecine methyl ester, tyrosine derivative, pregabalin LYRICA^®, Boc-Amantidine, flutamide, aminocyclopentane carboxylic acid, ibuprofen, ibuprofen methyl ester, rasagiline, nabumetone, celecoxib analog, papaverine, protected enalaprilat, protected fingolimod, protected dopamine, N-Boc-cinacalcet, JNJ41510417, 5-OH- FPPAT, FEP, Acl703. BMIPP, HAR, flutemetamol, MK-9470, FACPC, CURB, MFES, FES, 2-ME, PHNO, PHNO, fallypride, DMFP, 5-OH-FPPAT, 5-OH- DPAT, NPA, NNC112, SCH, FDA, MNP A, MC113, SA4503, SA6298, BMS- 747158-01, PBR28, PBR06, FMPEP, MePPEP, FBzBMS, FBFPA, FEPPA, telmisartan, tacrine, desloratadine, etodolac, cinacalcet, tanshinone IIA, indomethacin, trimethoprim, masoprocol, dubutamine, duloxetine, ondansetron, benzbromarone, simple alkanes, neopentane, toluene, cyclohexane, norcarne, simple hydrocarbons, neopentane, toluene, cyclohexane, norcarane, ircms- decalin; 5a-cholestane, sclareolide, 1, 3, 5(10)-estratrien-17-one, (lR,4aS, 8aS)-octahydro- 5,5,8a-trimethyl-l-(3-oxobutyl)-naphtalenone, (1R, 4S, 6S, 10S)-4, 12, 12- trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one, levomethorphan, lupine, 20-methyl- 5alpha(H)-pregnane, isolongifolanone, caryophyllene acetate, N-acetyl- gabapentin methyl ester, acetyl-amantidine, phthalimido-amantadine, methyloctanoate, saturated fatty acid esters, N-acetyl-Lyrica methyl ester, artemisinin, adapalene, finasteride, N-acetyl-methylphenidate, mecamylamine, N-acetyl-mecamylamine, N-acetyl-memantine, phthalimidi-memantine, N- acetyl-enanapril precursor methyl ester, progesterone, artemisinin, adapalene, dopamine derivative, pregabalin, cholestane, finasteride, methylphenidate derivative, mecamylamine, gabapentin, memantine derivative, gabapentin, rimantadine derivative, isoleucine derivative, leucine derivative, valine derivative, progesterone, tramadol, enalapril precursor, (1R, 4aS, 8aS)-5, 5, 8a-

-44- trimethyl- l-(3-oxobutyl)octahydronaphthalen-2(lH)-one, phenylalanine donepezil precursor, amphetamine, δ-tocopherol form of vitamin E, tyrosine, melatonin, tryptophan, estrone acetate, progesterone, dopamine, homophenylalanme, DOPA, ibuprofen methyl ester, buspirone, eticyclidine, memantine, amantadine, lubiprostone, penridopril, fosinopril, N-Phth amantadine, N-Phth Memantine; 2- adamantanone, rimantadine analogue, adapalene precursor, perindopril precursor, protected gabapentin, methyl octanoate, methyl nonanate, methyl hexanoate, cyclohexyl acetate, cyclohexane carboxylic acid methyl ester, and an analog of any one of the foregoing.

56. The composition of embodiment 54, wherein the carbon containing compound is a monofluoro containing compound having an sp3 C-H bond.

57. A composition comprising any fluorinating catalyst herein.

58. A composition comprising the product of any reaction herein.

59. The composition of any one of embodiment 42 - 58 further comprising a pharmaceutically acceptable carrier.

60. A composition comprising at least one compound selected from the group consisting of: [¹⁸F]-fluoro-inhibitors of cyclooxygenase (COX), [¹⁸F]-fluoro- inhibitors of monoamine oxidase B (MAO-B), [¹⁸F]-fluoro-inhibitors of phosphodiesterase 10A (PDEIOA), [¹⁸F]-fluoro-inhibitors of angiotensin-converting enzyme (ACE), [¹⁸F]-fluoro-bio-messenger molecules, the neurotransmitter [¹⁸F]- fluoro- dopamine, [¹⁸F]-fluoro-fingolimod, [¹⁸F]-fluoro-Leucine- derivatives, [¹⁸F]- fluoro- Valine -derivatives, [¹⁸F]-fluoro-Leucine dipeptide, [¹⁸F]-fluoro-Boc-Valine- Luecine methyl ester, [¹⁸F]-fluoro-tyrosine derivative, [¹⁸F]-fluoro-pregabalin LYRIC A^®, [¹⁸F]-fluoro-Boc-Amantidine, [¹⁸F]-fluoro-flutamide, [¹⁸F]-fluoro- aminocyclopentane carboxylic acid, [¹⁸F]-fluoro-ibuprofen or the methyl ester thereof, [¹⁸F]-fluoro-rasagiline, [¹⁸F]-fluoro-nabumetone, [¹⁸F]-fluoro-celestolide,

-45- [¹⁸F]-fluoro-celecoxib analog, [¹⁸F]-fluoro-papaverine, [¹⁸F]-fluoro-protected enalaprilat, [¹⁸F]-fluoro-protected fingolimod, [¹⁸F]-fluoro-protected dopamine, [¹⁸F]-fluoro-N-Boc-cinacalcet, [¹⁸F]-fluoro-JNJ41510417, [¹⁸F]-fluoro-5-OH- FPPAT, [¹⁸F]-fluoro-FEP, [¹⁸F]-fluoro-Acl703, [¹⁸F]-fluoro-BMIPP, [¹⁸F]-fluoro- HAR, [¹⁸F]-fluoro-flutemetamol, [¹⁸F]-fluoro-MK-9470, [¹⁸F]-fluoro-FACPC, [¹⁸F]- f uoro-CURB, [¹⁸F]-fluoro-MFES, [¹⁸F]-fluoro-FES, [¹⁸F]-fluoro-2-ME, [¹⁸F]-fluoro- PHNO, [¹⁸F]-fluoro-PHNO, [¹⁸F]-fluoro-fallypride, [¹⁸F]-fluoro-DMFP, [¹⁸F]-fluoro- 5-OH-FPPAT, [¹⁸F]-fluoro-5-OH-DPAT, [¹⁸F]-fluoro-NPA, [¹⁸F]-fluoro-NNCll2, [¹⁸F]-fluoro-SCH, [¹⁸F]-fluoro-FDA, [¹⁸F]-fluoro-MNPA, [¹⁸F]-fluoro-MCll3, [¹⁸F]- fluoro-SA4503, [¹⁸F]-fluoro-SA6298, [¹⁸F]-fluoro-BMS-747158-01, [¹⁸F]-fluoro- PBR28, [¹⁸F]-fluoro-PBR06, [¹⁸F]-fluoro-FMPEP, [¹⁸F]-fluoro-MePPEP, [¹⁸F]- fluoro-FBzBMS, [¹⁸F]-fluoro-FBFPA, [¹⁸F]-fluoro-FEPPA, [¹⁸F]-fluoro-telmisartan, [¹⁸F]-fluoro-tacrine, [¹⁸F]-fluoro-desloratadine, [¹⁸F]-fluoro-etodolac, [¹⁸F]-fluoro- cinacalcet, [¹⁸F]-fluoro-tanshinone IIA, [¹⁸F]-fluoro-indomethacin, [¹⁸F]-fluoro- trimethoprim, [¹⁸F]-fluoro-masoprocol, [¹⁸F]-fluoro-dubutamine, [¹⁸F]-fluoro- duloxetine, [¹⁸F]-fluoro-ondansetron, [¹⁸F]-fluoro-benzbromarone, simple [¹⁸F]- fluoro-alkanes, [¹⁸F]-fluoro-neopentane, [¹⁸F]-fluoro-toluene, [¹⁸F]-fluoro- cyclohexane, [¹⁸F]-fluoro-norcarne, simple [¹⁸F]-fluoro-hydrocarbons, [¹⁸F]-fluoro- trans-decalin, [¹⁸F]-fluoro-5a-cholestane, [¹⁸F]-fluoro-sclarolide, [¹⁸F]-fluoro-l, 3, 5(10)-estratrien-17-one, [¹⁸F]-fluoro-(lR,4aS, 8aS)-octahydro-5,5,8a-trimethyl-l- (3-oxobutyl)-naphtalenone, [¹⁸F]-fluoro-(lR, 4S, 6S, 10S)-4, 12, 12-trimethyl- tricyclo[8.2.0.04,6]dodecan-9-one, [¹⁸F]-fluoro-levomethorphan, [¹⁸F]-fluoro- lupine, [¹⁸F]-fluoro-20-methyl-5alpha(H)-pregnane, [¹⁸F]-fluoro-isolongifolanone, [¹⁸F]-fluoro-caryophyllene acetate, [¹⁸F]-fluoro-N-acetyl-gabapentin methyl ester, [¹⁸F]-fluoro-acetyl-amantidine, [¹⁸F]-fluoro-phthalimido-amantadine, [¹⁸F]-fluoro- methyloctanoate, other saturated [¹⁸F]-fluoro-fatty acid esters, [¹⁸F]-fluoro-N- acetyl-Lyrica methyl ester, [¹⁸F]-fluoro-artemisinin, [¹⁸F]-fluoro-adapalene, [¹⁸F]- fluoro-finasteride, [¹⁸F]-fluoro-N-acetyl-methylphenidate, [¹⁸F]-fluoro- mecamylamine, [¹⁸F] -fluoro-N-acetyl-mecamylamine, [¹⁸F] -f uoro-N-acetyl- memantine, [¹⁸F]-fluoro-phthalimidi-memantine, [¹⁸F]-fluoro-N-acetyl-Enanapril precursor methyl ester, [¹⁸F]-fluoro-progesterone, [¹⁸F]-fluoro-artemisinin, [¹⁸F]-

-46- fluoro-adapalene, [¹⁸F]-fluoro-dopamine derivative, [¹⁸F]-fluoro-pregabalin, [¹⁸F]- fluoro-cholestane, [¹⁸F]-fluoro-finasteride, [¹⁸F]-fluoro-methylphenidate derivative, [¹⁸F]-fluoro-mecamylamine, [¹⁸F]-fluoro-gabapentin, [¹⁸F]-fluoro- memantine derivative, [¹⁸F]-fluoro-isoleucine derivatives, [¹⁸F]-fluoro- progesterone, [¹⁸F]-fluoro-tramadol and [¹⁸F]-fluoro-(lR, 4aS, 8aS)-5, 5, 8a- trimethyl-l-(3-oxobutyl)octahydronaphthalen-2(lH)-one, or pharmaceutically acceptable salts or solvates thereof.

61. A composition comprising a difluoro containing compound.

62. The composition of embodiments 60 or 61 further comprising a pharmaceutically acceptable carrier.

63. The composition of any one or more of embodiment 60— 62 or 66, wherein the pharmaceutically acceptable carrier includes one or more agent selected from the group consisting of carrier, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, human serum albumin, buffer substances, phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, waxes, polyethylene glycol, starch, lactose, dicalcium phosphate, microcrystallme cellulose, sucrose, talc, magnesium carbonate, kaolin, non-ionic surfactants, edible oils, physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) and phosphate buffered saline (PBS).

64. The composition of one or more of embodiments 60 - 63, wherein the at least one compound is fluoro-rasagiline, and the composition further comprises levodopa or a pharmaceutically acceptable salt or solvate thereof.

-47- 65. A composition comprising at least one compound selected from the ^roup consisting of

Compound

Compound

Compound

Compound

Compound

Compound

Compound

Compound

Compound

Compound

Compound

Compound

13 ;

-48- Compound 1

Compound 1

Compound 1

Compound 1

Compound 1

Compound 1

Compound 20

Compound 21

Compound 22

Diastereomer

Diastereomer

Compound 24

-49- Compound

Compound

Compound

Compound

Compound

Compound

Compound

Compound 32

.

Compound 33

-50- 467

PCT/US2015/018446

Compound 34

COOMe

Compound 35 MeOOC

Compound 36

Compound 37

Compound 38

Compound 39

Compound 40

-51- Compound 41

Compound 42

Compound 43

Compound 44 CI

Compound 45

Compound 46

Compound 47

;

-52- Compound 48

Compound 49

Compound

Compound 51

Compound 52

-53-

Compound 57

Compound 58

Compound 59

Compound 60

Compound 61

or pharmaceutically acceptable salts or solvates thereof, wherein the F in each compound is ¹⁸F.

-54- 66. The composition of embodiment 65 further comprising a pharmaceutically acceptable carrier.

[0086] Further embodiments herein may be formed by supplementing an embodiment with one or more element from any one or more other embodiment herein, and/or substituting one or more element from one embodiment with one or more element from one or more other embodiment herein.

[0087] Examples— The following non-limiting examples are provided to illustrate particular embodiments. The embodiments throughout may be supplemented with one or more detail from one or more example below, and/or one or more element from an embodiment may be substituted with one or more detail from one or more example below.

[0088] As discussed herein, substrates and targets are carbon containing compounds that may be ¹⁸F fluorinated by the methods herein.

[0089] Example 1 - ¹⁸F labeling method for aliphatic C-H bonds with no- carrier-added [¹⁸F]fluoride

[0090] The late-stage ¹⁸F labeling method for aliphatic C-H bonds with no-carrier-added [¹⁸F]fluoride is described herein. The method allows the facile labeling of a variety of bioactive molecules with radiochemical yields ranging from 20% to 72% within 10 minutes without the need for pre-activation of the labeling target. Notably, an acetone solution of the catalyst, Mn(salen)OTs, can directly elute [¹⁸F] fluoride from an ion exchange cartridge with over 90% efficiency. Using this feature, the conventional and laborious dry-down step prior to reaction is circumvented, greatly simplifying the mechanics of this protocol and shortening the time for automated synthesis. With all these appealing characteristics, this ¹⁸F labeling method is expected to have broad applications in drug development, PET imaging and high-throughput radiotracer identification.

[0091] FIG. 1A illustrates methods currently available for ¹⁸F labeling.

Referring to this fugure, the traditional methods are dominated by a "pre-

-55- functionalization" approach in which a highly reactive chemical functional group (L) is preinstalled at the labeling site and substituted later by ¹⁸F. In most cases, multistep synthesis is required for the preparation of the "pre- activated" precursor (Ametamey, S. M. et al., Chem. Rev. 2008, 108, 1501). Consequently, potential radiotracer candidates are often prioritized for radiolabeling based on synthetic accessibility of the precursor, which amplifies dramatically with increasing structural complexity. Frequently, harsh conditions (e.g. high temperatures) are required for the ¹⁸F labeling step, which can further diminish the functional group compatibility of reaction (Tredwell, M.; Gouverneur, V. Angew. Chem. Int. Ed. 2012, 51, 11426; Hollingworth, C; Gouverneur, V. Chem. Commun. 2012, 48, 2929). The drawback of the "pre- functionalization" approach is most evident in the screening of PET tracers, where labeling of a diverse range of molecules is desired. Thus, iterative discovery through trial and error is adopted, which is slow due to arduous precursor synthesis for each radiotracer candidate (Agdeppa, E. D.; Spilker, M. E. AAPS J. 2009, 11, 286). Much synthesis work goes into precursor preparation and radiolabeling that is essentially wasted. A relatively simple set of imaging experiments can 'fail' a compound from moving forward, usually due to lack of uptake in the target location or the determination that uptake is nonspecific.

[0092] FIG. IB illustrates an ¹⁸F labeling strategy that implements a direct replacement of sp³ hydrogen with fluorine. The method avoids the need for target pre-activation, enabling high throughput radiolabeling of parent compounds and building blocks. A set of reaction conditions will be developed that would allow for choice of ¹⁸F labeling at a variety of the ubiquitous C-H bond locations in organic molecules. A selective ¹⁸F substitution at benzylic C-H bonds, which is common to drug and drug-like molecules, was demonstrated. The method shows promise to significantly increase the efficiency of PET tracer synthesis and evaluation and provide ready access to labeled molecules that are difficult to access or cannot be prepared by conventional methods.

-56- [0093] The concept of direct hydrogen substitution with ¹⁸F was first demonstrated by Firnau et al. in 1980s (Firnau, G. et al., J. Nucl. Med. 1984, 25, 1228, which is incorporated by reference herein as if fully set forth). This work reported the use of [¹⁸F]F2 or its derivative [¹⁸F]CH3COOF for the direct electrophilic radiofluorination of aromatic rings. The application of [¹⁸F]F2 or [¹⁸F]CH3COOF for broad radio labeling applications is restricted, due to their low functional group tolerance, lack of operational simplicity and notoriously low specific activity. There has been very limited development of ¹⁸F labeling methods based on C-H fluorination since this pioneering work.

[0094] A series of manganese-catalyzed aliphatic C-H fluorination reactions exhibit promising features for ¹⁸F labeling applications (Liu, W.; Huang, X.; Groves, J. T. Nat. Protoc. 2013, 8, 2348; Liu, W.; Groves, J. T. Angew. Chem. Int. Ed. 2013, 52, 6024; Liu, W.; Huang, X.; Cheng, M.-J.; Nielsen, R. J.; Goddard, W. A., Ill; Groves, J. T. Science 2012, 337, 1322, all of which are incorporated by reference herein as if fully set forth). These reactions utilize nucleophilic fluoride (F ) as fluorine source, in contrast to methods that require reactive, electrophilic fluorinating agents. The method was shown to proceed through a novel fluoromanganese(IV) fluorine transfer intermediate that efficiently traps intermediate substrate radicals via fluorine atom transfer. Thus, fluoride ion coordination to the manganese catalyst has produced a new type of fluorinating agent that is amenable to late- stage fluorinations of C-H bonds in complex bioactive molecules.

[0095] The pivotal factor for adapting fluoromanganese(IV) fluorine transfer reactions to ¹⁸F labeling was the formation of reactive ¹⁸F-containing intermediates using sub-stoichiometric, low- concentration [¹⁸F]fluoride. Under catalytic ¹⁹F reaction conditions, excess fluoride was used, serving two critical roles (Liu, W.; Groves, J. T. Angew. Chem. Int. Ed. 2013, 52, 6024; Liu, W.; Huang, X.; Cheng, M.-J.; Nielsen, R. J.; Goddard, W. A., Ill; Groves, J. T. Science 2012, 337, 1322, both of which are incorporated by reference herein as if fully set forth). The first is to act as the axial ligand for the oxomanganese(V) species in the hydrogen abstraction step, slowing down the hydroxyl rebound

-57- rate of the substrate radical to the hydroxomanganese(IV) intermediate. The second role of fluoride is to form the fluorinating agent, fluoromanganese(IV). To address this challenge in the context of radiochemistry, it was hypothesized that [¹⁸F]fluoride association to manganese would be more facile if the chloride ligand of the Mn(salen)Cl catalyst was replaced by weakly-coordinating anions.

[0096] To test this hypothesis, a set of the exploratory conditions was employed to evaluate the efficacy of various manganese salen catalysts for ¹⁸F labeling. Table 1 shows optimization of aliphatic C-H ¹⁸F fluorination of ibuprophen. It was found that while Mn(salen)Cl gave only trace amounts of ¹⁸F-labeled product, manganese salen complexes with more labile triflate (OTf) or perchlorate counter ions showed substantial higher radiochemical conversions (RCC) to ¹⁸F-labeled product 2 (16% and 34%, respectively). Various more weakly associated ligands were evaluated and p-toluenesulfonate (OTs) was found to afford the highest RCC (53%) in the test reaction. Further optimizations based on the Mn(salen)OTs catalyst achieved a maximum of 65% RCC for the initial substrate (ibuprofen) using iodosylbenzene (PhIO) as the oxidant (Table 1, Entry 5). No labeling products were detected in control experiments in which the manganese salen catalyst or iodosylbenzene were omitted.

[0097] Table 1. Optimization of aliphatic C-H ¹⁸F-fluorination of ibuprofen. OMe Cat. (10 mol%) OMe

PhIO (1 equiv.)

[¹⁸F]F (no-carrier added)

solvent, T( °C), 10 min

Catalyst Solvent T (°C) RCC

Mn(salen)Cl ACN 50 trace

2 Mn(salen)OTf ACN 50 16%

3 Mn(salen)C10₄ ACN 50 34%

4 Mn(salen)OTs ACN 50 53%

5 Mn(salen)OTs Acetone 50 65%

6 Mn(salen)OTs Acetone 25 45%

7 Mn(salen)OTs Acetone 90 50%

-58- [0098] FIG. 2 illustrates that that this fluorination reaction allowed for the efficient ¹⁸F labeling of benzylic C-H bonds in a wide range of substrates with RCC ranging from 20% to 68%. Referring to this figure, it was found that a variety of functional groups was well tolerated, including esters, amides, imides, ketones, alkynes, ethers, cyanides, heterocycles, carbamates, aryl and aliphatic halides. Still referring to FIG. 2, the labeling was generally more efficient for substrates bearing electron- donating groups, presumably due to the electrophilic nature of the hydrogen-abstracting oxomanganese(V) intermediate. The method can be used to prepare ¹⁸F-labeled synthons (in addition to direct labeling for radiotracer evaluation). Still referring to FIG. 2, for example, dibenzosuberone (10), the chemical precursor of a series of tricyclic antidepressant drugs (TCAs) including amitriptyline and nortriptyline, was readily labeled with ¹⁸F in 50% RCC. The tolerance of reactive functional groups such as halogens and alkynes enables the rapid incorporation of ¹⁸F- labeled motifs into complex structures through well-established methods such as nucleophilic substitutions or "click" reactions (Marik, J.; Sutcliffe, J. L. Tetrahedron Lett. 2006, 47, 6681, which is incorporated herein by reference as if fully set forth). Notably, the ¹⁸F labeling reaction can be performed under air and without rigorous exclusion of water, greatly simplifying the protocol and facilitating scale-up.

[0099] The major benefit of this mild C-H ¹⁸F-fluorination reaction is its application to late- stage radiolabeling. To demonstrate this potential, a variety of well-known biologically active molecules was examined. FIG. 3 illustrates the selected molecules that encompass inhibitors of important biological and pharmacological targets including cyclooxygenase (COX), monoamine oxidase B (MAO-B), phosphodiesterase 10A (PDEIOA) and angiotensin- converting enzyme (ACE), as well as bio-messenger molecules such as the neurotransmitter dopamine, and the immuno-modulating drug, fingolimod. Subjecting these molecules (or protected analogs) to Mn-catalyzed fluorination led to successful ¹⁸F labeling specifically at benzylic positions. Referring to this figure, it was observed that the RCC ranged from 22% to 72% at 50 °C within 10 min. Still

-59- referring to FIG. 3, in the case of fingolimod, 29, high regioselectivity was observed for the protected amino diol side chain. Notably, the ¹⁸F labeling reaction showed much broader substrate scope than its ¹⁹F counterpart. Still referring to FIG. 3, for example, fluorinating C-H bonds β to electron- withdrawing groups (e.g., a ketone or Boc-protected amine) was very challenging on a preparative scale in the ¹⁹F reaction (24 and 30), but this position was readily labeled under ¹⁸F reaction conditions with RCC of 41% and 51%, respectively, for 24 and 30. This seemingly counterintuitive phenomenon results from the very low concentration of [¹⁸F]fluoride and the large excess of manganese catalyst. Apparently, the small amounts of manganese fluorides present under ¹⁸F labeling conditions are sufficient to capture the incipient substrate radicals with high efficiency in terms of the amount of [¹⁸F]fluoride.

[00100] Additional compounds that could be labeled with the method described herein are illustrated in FIGS. 4A - 4H.

[00101] After the enabling power of ¹⁸F fluorination protocol was demonstrated, initial process optimization was performed to facilitate scale-up for PET imaging. While the method is compatible with typical "dry-down" procedures used in ¹⁸F chemistry, it was surprisingly discovered that no drying procedure was required. [¹⁸F] Fluoride (6 mCi) deposited on an anion exchange cartridge (AEC) could be eluted using an organic solution of the catalyst, Mn(salen)OTs with 90% recovery of the radiolabel from the column and no erosion of the RCC in the subsequent fluorination reaction. FIG. 5 illustrates that "dry -down" procedure, in which ¹⁸F-labeled celestolide with 30% RCC was obtained from the subsequent reaction. This operationally simple, dry down- free protocol could be readily scalable for automated synthesis.

[00102] It is of interest to compare and contrast the ¹⁸F fluorinations described here using limiting fluoride ion to the ¹⁹F reactions that was previously described that use a large excess of fluoride. FIG. 6A illustrates the mechanism for this ¹⁸F labeling reaction. Referring to this figure, tosylate replacement via ligand metathesis in Mn(salen)OTs would serve first to trap the [¹⁸F]fluoride forming [¹⁸F]Mn(salen)F. which is then oxidized by PhIO to

-60- form the hydrogen abstraction intermediate [¹⁸F]oxoMn^v(salen)F (32). Subsequent C-H abstraction by this reactive oxomanganese(V) species would afford the substrate radical and ¹⁸F-Mn^IV-OH intermediate (33). The final step would be the formation of the product C-¹⁸F bond by fluorine transfer from 33 to the substrate radical. Although the proposed mechanism resembles the catalytic cycle of ¹⁹F reaction, a major difference lies in the fluorine transfer step. In ¹⁹F chemistry, a t rans- difluoromanganese(IV) complex was shown to be the reactive fluorine transfer intermediate. This compound was isolated and structurally characterized (Liu, W.; Huang, X.; Cheng, M.-J.; Nielsen, R. J.; Goddard, W. A., Ill; Groves, J. T. Science 2012, 337, 1322, which is incorporated herein by reference as if fully set forth). However, due to the limiting amount of [¹⁸F]fluoride in the labeling conditions, the formation of [^lsF]trans- difluoromanganese(IV) intermediate from complex 33 is not feasible. Therefore, the [¹⁸F] fluorine transfer is very likely to proceed directly through a ¹⁸F-Mn^IV- OH intermediate even in the presence of a large excess of manganese catalyst that has no fluoride ligand.

[00103] FIG. 6B illustrates the involvement of a manganese salen-bound ¹⁸F intermediate in the fluorine transfer step that was demonstrated experimentally by analyzing the enantioselectivity of the resulting ¹⁸F-labeled product. Referring to FIG. 6B, using celestolide as the diagnostic substrate a 25% ee was measured in the fluorinated product using chiral HPLC analysis and radio- detection. FIGS. 37A and 37B illustrate the effect of the catalyst. It was observed that when the catalyst was changed from (R,R)-Mn(salen)OTs (FIG. 37A) to (S,S)-Mn(salen)OTs (FIG. 37 B), the same 25% ee was observed in the labeling product but with reversed enantioselectivity. FIG. 6C illustrates the fluorine transfer reactivity of the ¹⁸F-Mn^IV-OH complex was confirmed by density by theory (DFT) computations. Referring to FIG. 6C, it was observed that the activation barrier of fluorine transfer from F-Mn^IV-OH complex (34) to benzyl radical was only 9.6 kcal/mol in an acetone solvent continuum. Still referring to FIG. 6C, the molecular orbitals involved in the C-F bond formation are the o*(z²) orbital of 34 and the benzyl radical SOMO. The overall fluorine

-61- transfer process is thermodynamically favored with a calculated free energy change of -38.0 kcal/mol.

[00104] Representative, non-limiting Mater als

[00105] Substrates of products 2, 13, 17, 20, 23, 28, 30 were purchased from commercial sources and were protected according to the literature procedure (Jiang, M. Y.; Dolphin, D. Journal of the American Chemical Society 2008, 130, 4236; Selvakumar, J.; Ramanathan, C. R. Organic & Biomolecular Chemistry 2011, 9, 7643; Young, D. D.; Connelly, C. M.; Grohmann, C; Deiters, A. Journal of the American Chemical Society 2010, 132, 7976, all of which are incorporated herein by reference as if fully set forth). Substrates of 26 and 31 were synthesized as previously described (Ahlstroem, M. M.; Ridderstroem, M.; Zamora, I.; Luthman, K. Journal of Medicinal Chemistry 2007, 50, 4444; Bijukumar, G.; Maloyesh, B.; Bhaskar, B. S.; Rajendra, A. Synthetic Communications 2008, 38, 1512, both if which are incorporated herein by reference as if fully set forth).

[00106] Iodosylbenzene (PhIO) was prepared by hydrolysis of iodobenzene diacetate with sodium hydroxide solution. Mn(salen)OTs was prepared from Mn(salen)Cl and AgOTs. Substrate of 29 was purchased from Matrix Scientific. Other purchased materials were of the highest purity available from Aldrich and used without further purification. ^XH NMR spectra were obtained on a Bruker NB 300 spectrometer or a Bruker Avance-III (500 MHz) spectrometer and are reported in ppm using solvent as an internal standard (CDCI3 at δ 7.26, acetone-d6 at2.04, or methylene chloride-cfeat 5.32). Data reported as: chemical shift (δ), multiplicity (s= singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz); integrated intensity. ¹³C NMR spectra were recorded on a Bruker 500 (125 MHz) spectrometer and are reported in ppm using solvents as an internal standard (CDCI3 at 77.15 ppm, acetone-d6 at 29.92 ppm, or methylene chloride-cfe at 54.0). ¹⁹F NMR spectra (282 MHz) were obtained on a Bruker NB 300 spectrometer and were referenced relative to relative to CFCI3. GC/MS analyses were performed on an Agilent 7890A gas chromatograph equipped with an Agilent 5975 mass selective detector. High-

-62- resolution mass spectra were obtained from the Princeton University mass spectrometer facility by electrospray ionization (ESI). High-performance liquid chromatography (HPLC) was performed on an Agilent 1100 series instrument with a binary pump and a diode array detector.

[00107] Radiochemistry

[00108] No-carrier-added [¹⁸F]fluoride was produced from water 97% enriched in ¹⁸0 (ISOFLEX, USA) by the nuclear reaction ¹⁸0(p,n)¹⁸F using a Siemens Eclipse HP cyclotron and a silver-bodied target at Massachusetts General Hospital Athinoula A. Martinos Center for Biomedical Imaging. The produced [¹⁸F] fluoride in water was transferred from the cyclotron target by helium push.

[00109] Radiosynthesis of ¹⁸F labeled molecules

[00110] A 4 mL vial with a screwed cap was charged with Mn(salen)OTs (17 mg, 0.022 mmol), substrate (0.25 mmol) and a stir bar (2 5 mm). A portion of aqueous [¹⁸F]fluoride solution (40 - 50

4 - 5 mCi) obtained from a cyclotron was loaded on to an Chromafix PS-HCO3 IEX cartridge, which had been previously washed with 5.0 mg/mL K2CO3 in Milli-Q water followed by 5 mL of Milli-Q water. Then, the cartridge loaded with [¹⁸F]fluoride was washed with 2 mL Milli-Q water and [¹⁸F]fluoride was released from the cartridge using 0.8 mL 5.0 mg/mL K2CO3 in Milli-Q water. A portion of the resulting [¹⁸F]fluoride solution (25μΕ, 125 - 150 μϋί) was diluted with 3.0 mL acetone. 0.6 mL of this [¹⁸F]fluoride acetone solution was added to the vial containing the catalyst and the substrate. The resulting solution was stirred for 1 min at room temperature. Then 55 mg (0.25 mmol) iodosylbenzene (PhIO) was added to the solution, and the vial was capped and stirred at 50 °C for 10 min. After 10 min, aliquot of the reaction mixture was taken and spot on a silica gel TLC plate. The plate was developed in an appropriate eluent and scanned with a Bioscan AR-2000 Radio TLC Imaging Scanner.

[00111] Example 2 - "dry-down" free procedure for radiosynthesis of ¹⁸F labeled molecules

-63- [00112] A 4 mL vial with a screwed cap was charged with substrate (0.33 mmol) and a stir bar (2 5 mm). A portion of aqueous [¹⁸F]fluoride solution (40 - 50 4 - 5 mCi) obtained from a cyclotron was loaded on to an Chromafix PS-HCO3 IEX cartridge, which had been previously washed with 5.0 mg/niL K2CO3 in Milli-Q water followed by 5 mL of Milli-Q water. Then the cartridge was washed with 2 mL anhydrous acetonitrile for three times. The [¹⁸F]fluoride was released using 0.8 mL acetone solution of Mn(salen)OTs (23 mg, 0.030) mmol (> 90% radioactivity being eluted). The obtained solution was added to the vial containing the substrate and 60 mg of PhIO was added. The vial was capped and stirred at 50 °C for 10 min. After 10 min, aliquot of the reaction mixture was taken and spot on a silica gel TLC plate. The plate was developed in an appropriate eluent and scanned with a Bioscan AR-2000 Radio TLC Imaging Scanner. Any fluorinating catalyst described herein may replace Mn(salen)OTs if desired. FIGS. 7A - 7H illustrate exemplary TLC scans for respective Compounds 2, 23, 25, 27, 28, 29, 30 and 31.

[00113] Example 3 - radio-HPLC characterization of the ¹⁸F labeled products of Compounds 2 - 31

[00114] The ¹⁸F-labeled molecules were characterized by comparing the radio-HPLC trace of the crude reaction mixture to the HPLC UV trace of the authentic reference sample, with methods detailed below. There are time difference (At) between the radio-HPLC trace and the HPLC UV trace due to the delay volume (time) between the diode array detector and the radioactivity detector (for 0.5 ml/min flow rate, At ~ 0.16 min, for 1.0 ml/min flow rate, At ~ 0.35 min). The reaction was performed the following methods: Method A ( HPLC column: Agilent Eclipse XDB-C18, 5 μπι, 4.6 x 150 mm. Gradient: H₂0 (0.1% TFA, A) and ACN (0.1% TFA, B), 0-3 minutes, 5% B; 3-6 minutes, 50% B; 6-9 minutes, 95% B, 1.0 ml/min), Method B (HPLC column: Angilent ZORBAX Rx-SIL 5um, 4.6 x 150mm. Gradient: 2% isopropanol (IPA) to 98% hexanes, isocratic, 0.5 ml/min), Method Bl (HPLC column: Angilent ZORBAX Rx-SIL 5um, 4.6 x 150mm. Gradient: 3% IPA to 97% dichloromethane (DCM), isocratic,

-64- 0.5 ml/min), Method B2 (HPLC column: Angilent ZORBAX Rx-SIL 5um, 4.6 x 150mm. Gradient: 5% IPA to 95 DCM, isocratic, 0.5 ml/min), Method C(HPLC column: Agilent Eclipse XDB-C18, 5 μηι, 4.6 x 150 mm. Gradient: 70% pure ACN to 30% pure water, isocratic, 0.5 ml/min). FIGS. 8 - 36 illustrate comparison of the radio -HPLC traces to the HPLC UV traces for reference samples of Compounds 2 - 19 and 21 - 31, respectively.

[00115] Example 4 - enantiodiscriminating radio-HPLC trace of celestolide [00116] The analysis was performed using radio-HPLC gradient: 2% IPA/98% hexanes, isocratic, column: analytical Chiralcel OD column. FIG. 37A illustrates enantoselectivity of the resulting ¹⁸F labeled product of the reaction catalyzed by (R,R)-Mn(salen)OTs. FIG. 37B illustrates enantoselectivity of the resulting ¹⁸F labeled product of the reaction catalyzed by (<S,S)-Mn(salen)OTs.

[00117] Example 5 -preparation and characterization of ¹⁹F authentic samples

[00118] This example provides further fluorinated compounds that may be in an embodiment herein, including compositions including any one or more of the fluorinated compounds. They may be ¹⁹F fluorinated compounds. The carbon containing compound of an embodiment herein may be one of the below compounds where an H is in place of F. Methods of making the compounds and methods of using these compounds are also embodiments herein. Those that are drugs may be implemented in methods of treatment. Those that are building blocks may be used to synthesize compounds containing fluorine.

[00119] As numbered below, compounds 24, 30, and 31 were prepared from the corresponding alcohols with DAST. Other compounds were prepared according to a manganese salen-catalyzed C-H fluorination procedure described herein. Namely, an oven- dried, 5 mL Schlenk flask was charged with a stir bar, Mn(Salen)Cl catalyst (100 mg, 0.16 mmol, 20 mol%) and substrate (0.8 mmol). The flask was evacuated and backfilled with N2 for three times. Under N2 atmosphere, TREAT HF (0.2 mL, 1.2 mmol, 1.5 equiv.) in 0.5 mL degassed

-65- CH3CN (0.5 niL) was added. The reaction mixture was then heated to 50°C. Under a stream of N2, iodosylbenzene (2.4 - 6.4 mmol, 3 - 8 equiv.) was added in small portions to the reaction mixture in solid form over a period of 3-8 h. The reaction progress was monitored by LC/MS or GC/MS. After the addition of iodosylbenzene was complete, the solution was allowed to cool to room temperature and products were separated from the reaction residue by silica gel column chromatography. Each compound could also be used as a building block to create drugs or other compounds containing fluorine. Further, each compound could be used to validate the presence of at least a portion of the compound in the drugs or other compounds containing ¹⁸F fluorine.

OMe

[00120] Compound 2

. Purification by column chromatography (10% EtOAc/hexanes). Ή NMR (500 MHz, CDCI3) 0.77 (d, J= 6.9 Hz, 3H), 0.94 (d, J= 6.8 Hz, 3H), 1.42 (dd, J= 7.3, 4.7 Hz, 3H), 2.01 (dh, J = 16.8, 6.7 Hz, 1H), 3.58 (s, 3H), 3.66 (q, J = 7.2 Hz, 1H), 5.00 (dd, J = 47.0, 6.9 Hz, 1H), 7.23 - 7.13 (m, 4H); ¹³C NMR (125 MHz, CDCI3) δ 17.6, 18.4, 18.6, 34.2, 34.4, 45.2, 52.1, 99.3, 126.46, 126.52, 127.5, 138.3, 140.7, 175.0; ¹⁹F NMR - 179.0 ppm; MS (EI) m/z ca 'd C14H19FO2 [M]⁺: 238.1, found 238.1.

[00121] Compound 3

. Purification by column chromatography (hexanes). Ή NMR (500 MHz, CDCI3) δ 1.65 (dd, J= 23.9, 6.4 Hz, 3H), 5.62 (dq, J = 47.5, 6.4 Hz, 1H), 7.32 - 7.18 (m, 2H), 7.62-7.47 (m, 2H); ¹³C NMR (125 MHz, CDCI3) δ 23.0, 90.4, 122.2, 127.0, 131.6, 140.5; ¹⁹F NMR -168.5 ppm; MS (EI) m/z cal'd C₈H₈BrF [ ⁺: 202.0, found 202.0.

[00122] Compound 4

. Purification by column chromatography (hexanes). ^XH NMR (500 MHz, CDCI3) δ 1.74 (dd, J= 23.8, 6.5 Hz, 3H), 5.80 (dq, J = 52.0, 6.3 Hz, 1H), 7.55 - 7.45 (m, 3H), 8.00 - 7.73 (m, 4H); ¹³C NMR (125 MHz, CDCI3) δ 23.1, 91.4, 123.3, 124.2, 126.2, 127.7, 128.1, 128.4, 128.8, 133.0,

-66- 138.8; ¹⁹F NMR -167.4 ppm; MS (EI) m/z cal'd C12H11F [M]⁺: 174.1, found

[00123] Compound 5

. Purification by flash chromatography

(hexanes). Ή NMR (300 MHz, CDCI3) δ 7.63 - 6.98 (m, 10H), 5.64 (ddd, J = 47.3, 8.1, 4.9 Hz, 2H), 3.57 - 2.76 (m, 2H); ¹³C NMR (75 MHz, CDCI3) 5139.8, 136.8, 129.6, 126.8, 128.5, 125.8, 95.0 (d, J = 174.3 Hz), 44.1 (d, J = 24.3 Hz); ⁱ⁹F NMR (282 MHz, CDCI3) -173.18 (ddd, J = 47.0, 28.8, 17.7 Hz); MS (EI) m/z cal'd C14H13F [M]⁺: 200.1,

[00124] Compound 6

. Purification by flash chromatography

(hexanes to 5% EtOAc/hexanes). ^XH NMR (300 MHz, CDCI3) δ 7.43 - 7.29 (m, 5H), 5.60 (ddd, J = 47.7, 8.6, 4.2 Hz, 1H), 2.01 (t, J = 2.6 Hz, 1H), 2.48 - 1.90 (m, 4H); ¹³C NMR (75 MHz, CDCI3) δ 139.8, 128.8, 128.6, 125.8, 125.7, 93.1 (d, J = 171.2 Hz), 83.2, 69.4, 36.2, 14.8; ¹⁹F NMR (282 MHz, CDCI3) -178.34 (ddd, J= 47.9, 30.0, 15.0 Hz); MS (EI) m/z cal'd CnHnF [M]⁺: 162.1, found 162.1.

[00125] Compound 7 Purification by flash chromatography (hexanes). ^XH NMR (500 MHz, CDCI3) 51.84 (dd, J= 23.8, 6.4 Hz, 3H), 6.37 (dq, J= 46.7, 7.0 Hz, 1H), 7.58 - 7.44 (m, 3H), 7.62 (d, J= 7.1 Hz, 1H), 7.91-7.82 (m, 2H), 8.02 (d, J = 7.6, 1H); ¹³C NMR (125 MHz, acetone-ds) 5 21.7, 88.6, 122.4, 123.4, 125.3, 125.8, 126.3, 128.7, 128.8, 130.0, 133.9, 137.3; ¹⁹F NMR -170.2 ppm; MS (EI) m/z cal'd C1 ⁺: 174.1, found 174.1.

[00126] Compound 8

. Purification by column chromatography (hexanes). Ή NMR (500 MHz, CDCI3) 5 1.54 (dd, J= 23.8, 6.4 Hz, 3H), 5.52 (dq, J = 47.5, 6.4 Hz, 1H), 7.34 - 7.15 (m, 4H); ¹³C NMR (125 MHz, CDCI3) 5 23.3, 90.5, 126.8, 128.9, 134.1, 140.0; ¹⁹F NMR -166.4 ppm; MS (EI) m/z cal'd CsHsCIF [M]⁺: 158.3, found 158.3.

-67- [00127] Compound

Purification by flash chromatography (hexanes). ^XH NMR (300 MHz, acetone-d₆) δ 7.58 (d, J= 5.7 Hz, 1H), 7.11 (d, J= 5.8 Hz, 1H), 5.52 (ddd, J = 47.4, 7.9, 5.7 Hz, 1H), 2.00 - 1.70 (m, 2H), 1.49 - 1.20 (m, 6H), 0.86 (m, 3H); ¹³C NMR (125 MHz, acetone-de) δ 141.1, 128.4, 126.8, 111.2, 90.1 (d, J = 167.9 Hz), 36.2, 32.1, 25.3, 23.2, 14.3; ¹⁹F NMR (125 MHz, acetone-de) -171.35 (ddd, J = 47.5, 26.3, 14.7 Hz, IF); MS (EI) m/z cal'd CioHi₄BrFS [M]⁺: 264.0, found 264.0.

[00128] Compound 10

. Purification by column chromatography (4% EtOAc/hexanes). Ή NMR (500 MHz, CDC1₃) δ 3.86 - 3.34 (m, 2H), 5.86 (ddd, J = 47.6, 9.7, 2.2 Hz, 1H), 7.70 - 7.19 (m, 6H), 8.28 - 7.93 (m, 2H); ¹³C NMR (125 MHz, CDCI3) δ 41.0, 90.5, 126.4, 127.5, 128.9, 130.2, 130.5, 130.6, 132.7, 132.8, 134.2, 136.2, 138.6, 139.2, 194.3; ¹⁹F NMR -168.8 ppm; MS (EI) m/z cal'd C15H11FO [M]⁺: 226.1, found 226.1.

[00129] Compound 11

. Purification by flash chromatography (hexanes to 10% EtOAc/hexanes). Ή NMR (300 MHz, acetone-de) δ 7.61 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 5.2 Hz, 1H), 6.03 (ddd, J = 51.7, 5.6, 3.5 Hz, 1H), 2.78 - 2.35 (m, 4H); ¹³C NMR (125 MHz, acetone-de) δ 191.8, 128.7, 125.2, 84.8 (d, J = 170.4 Hz), 34.4, 31.4; ¹⁹F NMR (125 MHz, acetone-de) -164.37 (ddd, J = 51.5, 26.0, 12.1 Hz, IF); MS (EI) m/z cal'd C₈H₇FOS [M]⁺: 170.0, found 170.0.

[00130] Compound 12 Purification by column chromatography

(hexanes). Ή NMR (300 MHz, Acetone-de) δ 7.66 - 7.49 (m, 2H), 7.46 - 7.33 (m,

2H), 5.71 (dq, J = 47.6, 6.4 Hz, 1H), 1.62 (dd, J = 23.9, 6.4 Hz, 3H); ¹³C NMR

(126 MHz, Acetone-de) δ 144.4, 131.1, 130.5, 128.1, 124.1, 122.0 , 89.8 (d, J =

168.0 Hz), 22.3; ¹⁹F NMR (282 MHz, Acetone-de) δ -169.49 (dq, J = 47.4, 23.7

Hz); MS (EI) m/z cal'd C₈H₈BrF [M]⁺: 202.0, found 202.0.

-68- [00131] Compound 13

. Purification by column chromatography (10% EtOAc/hexanes). Ή NMR (500 MHz, CDC1₃) δ 2.40 -

2.02 (m, 2H), 2.63 - 2.45 (m, 2H), 3.70 (s, 3H), 5.53 (ddd, J = 47.9, 7.6, 5.0 Hz,

1H), 7.52 - 7.34 (m, 5H); ¹³C NMR (125 MHz, CDCI3) δ 29.5, 32.3, 51.8, 93.4,

125.4, 128.4, 128.5, 139.6, 173.3; ¹⁹F NMR -178.1 ppm; MS (EI) m/z cal'd

C11H13FO2 [M]⁺: 196.1, found 196.1.

[00132] Compound 14

. Purification by flash chromatography

(hexanes to 20% EtOAc/hexanes). Ή NMR (300 MHz, CDCI3) δ 7.45 - 7.29 (m,

5H), 5.58 (ddd, J = 47.6, 8.4, 4.1 Hz, 1H), 2.63 - 2.07 (m, 4H). ¹³C NMR (125

MHz, CDCI3) 5138.3, 129.1, 128.9, 125.4, 119.0, 92.2 (d, J = 173.5 Hz), 33.0,

13.5. ¹⁹F NMR (282 MHz, CDCI3) -179.5 (ddd, J = 47.8, 28.5, 16.6 Hz); MS (EI) m/z cal'd C₁0H₁0FN [M]⁺: 163.1, found 163.1.

[00133] Compound 15

. Purification by column chromatography

(3%-20% EtOAc/hexanes). Ή NMR (500 MHz, CDCI3) δ 2.53 (m, 3H), 3.00 - 2.86 (m, 1H), 3.96 (s, 3H), 4.00 (s, 3H), 5.70 (dt, J=51.1, 4.5 Hz, 1H), 7.00 (s, 1H), 7.54 (s, 1H); ¹³C NMR (125 MHz, CDCI3) δ 30.0, 33.7, 56.2, 56.3, 88.0, 108.4, 109.5, 125.3, 135.0, 150.0, 154.0, 195.8; ¹⁹F NMR -169.6 ppm; HRMS (ESI) m/z cal'd C12H14FO3 [M+H]⁺: 225.0927, found 225.0924.

[00134] Compound 16

. Purification by column chromatography (hexanes). ^XH NMR (500 MHz, CDCI3) 51.63 (dd, J= 23.9, 6.4 Hz, 3H), 5.59 (dq, J = 47.5, 6.4 Hz, 1H), 7.20 - 7.06 (m, 2H), 7.80 - 7.70 (m, 2H); ¹³C NMR (125 MHz, CDCI3) 5 23.1, 90.5, 93.8, 127.3, 137.7, 141.3; ¹⁹F NMR -168.7 ppm; MS (EI) m/z cal'd C₈H₈FI [M]⁺: 250.0, found 250.0.

-69- [00135] Compound 17

Purification by column chromatography (10% EtOAc/hexanes). Ή NMR (500 MHz, CDC1₃) δ 2.69 - 2.00 (m, 2H), 3.92 (td, J = 7.2, 2.4 Hz, 2H), 5.56 (ddd, J= 47.9, 8.6, 4.2 Hz, IH), 7.44 - 7.29 (m, 5H), 7.77 - 7.67 (m, 2H), 7.85 (m, 2H); ¹³C NMR (125 MHz, CDCI3) δ 34.6, 35.7, 92.6, 123.2, 125.6, 128.5, 128.6, 132.0, 134.0, 139.3, 168.3; ¹⁹F NMR -175.7 ppm; MS (EI) m/z cal'd C17H14FNO2 [M]⁺: 283.1, found 283.1.

[00136] Compound 18

. Purification by column chromatography

(hexanes). Ή NMR (500 MHz, Acetone) δ 7.62 (dt, J= 8.1, 1.2 Hz, IH), 7.55 (dd, J= 7.8, 1.7 Hz, IH), 7.47 (td, J= 7.6, 1.2 Hz, IH), 7.30 (td, J= 7.7, 1.7 Hz, IH), 5.90 (dq, J = 46.7, 6.3 Hz, IH), 1.60 (dd, J = 23.9, 6.3 Hz, 3H). ¹³C NMR (126 MHz, Acetone) δ 141.8, 133.6, 130.9, 129.1, 127.4, 121.1, 90.6, 22.3 (s). ¹⁹F NMR -173.4 ppm; MS (EI) m/z ca 'd C₈H₈BrF [M]⁺: 202.0, found 202.0.

[00137] Compound 19

. Purification by flash chromatography

(hexanes, containing 1% gem-difluoride impurities) Ή NMR (500 MHz, CDCI3) δ 7.43 - 7.36 (m, 2H), 7.36 - 7.31 (m, 2H), 5.48 (ddd, J = 48.1, 8.0, 3.9 Hz, IH), 3.59 - 3.31 (m, 2H), 2.19 - 1.87 (m, 4H), 1.32 - 1.21 (m, IH), 0.93 - 0.76 (m, IH). 13C NMR (125 MHz, CDCI3) δ 139.8, 128.5, 125.4, 93.8 (d, J = 171.5 Hz), 35.7, 33.4, 28.3. ¹⁹F NMR (282 MHz, CDCI3) δ -176.03. MS (EI) m/z cal'd CioHi₂BrF [M]⁺: 230.0, fou 0.

[00138] Compound 20

^F3. Purification by column chromatography ( 10% EtOAc/hexanes). Ή NMR (500 MHz, CDCI3) δ 2.28 - 2.06 (m, 2H), 2.46 - 2.32 (m, 2H), 3.60 (ddd, J = 14.1, 12.3, 2.6 Hz, IH), 4.17 - 3.96 (m, IH), 5.48 (ddd, J = 50.9, 4.2, 2.5 Hz, IH), 7.23 (t, J = 7.4 Hz, IH), 7.37 - 7.31 (m, IH), 7.43 (d, J= 7.7 Hz, IH). 7.80 (br, IH); ¹³C NMR (125 MHz, CDCI3) δ 30.8, 41.1,

-70- 84.4, 116.4, 124.1, 126.7, 129.68, 129.71, 130.7, 136.5, 155.5; ¹⁹F NMR -68.8, 151.4 ppm; MS (EI) m/z cal'd C11H19F4NO [M]⁺: 247.1, found 247.1.

[00139] Compound 21 \= \=/ . Purification by column chromatography (hexanes). ^XH NMR (500 MHz, CDCI3) δ 1.60 (dd, J= 23.8, 6.4 Hz, 3H), 5.59 (dq, J= 47.7, 6.4 Hz, 1H), 7.42 - 7.22 (m, 4H), 7.57 - 7.45 (m, 5H); ¹³C NMR (125 MHz, CDCI3) δ 22.9, 90.7, 125.8, 127.1, 127.3, 127.5, 128.8, 140.7, 140.5, 141.3; ¹⁹F NMR -166.6 ppm; MS (EI) m/z cal'd C14H13F [M]⁺: 200.1, found 200.1.

[00140] Compound 22

. Purification by column chromatography (10% EtOAc/hexanes). Ή NMR (500 MHz, CDCI3) δ 1.66 (dd, J = 23.9, 6.4 Hz, 3H), 2.32 (s, 3H), 5.64 (dq, J = 47.6, 6.4 Hz, 1H), 7.20 - 7.04 (m, 2H), 7.46 - 7.35 (m, 2H); ¹³C NMR (125 MHz, CDCI3) δ 21.5, 23.0, 90.5, 121.8, 126.5, 139.0, 150.6, 169.6; ¹⁹F NMR -166.4 ppm; MS (EI) m/z cal'd C10H11FO2 [M]⁺: 182.1, found 182.1.

[00141] Compound 23. Purification by flash chromatography (hexanes to 5% EtOAc/hexanes). Two diastereomers 23a and 23b were separated as shown below.

00142 astereomer 23a F conta n ng two geometr ca somers n 2.8:1 ratio due to the amide moiety) Major isomer: Ή NMR (500 MHz, Methylene Chloride-d₂) δ 7.68 - 7.58 (m, 1H), 7.59 - 7.44 (m, 2H), 7.44 - 7.30 (m, 1H), 5.98 (ddd, J = 57.5, 7.3, 3.5 Hz, 1H), 5.52 (td, J= 7.8, 5.1 Hz, 1H), 5.36 (t, J = 1.1 Hz, 1H), 4.02 (dd, J = 17.2, 2.5 Hz, 1H), 3.74 (dd, J = 17.2, 2.5 Hz, 1H), 3.18 - 2.99 (m, 1H), 2.66 - 2.47 (m, 1H), 2.23 (t, J = 2.5 Hz, 1H); ¹³C NMR (126 MHz, Methylene Chloride-d₂) δ 156.4, 140.6, 138.7, 130.8, 130.0, 126.0, 125.1, 116.6 (q, J= 287.5), 92.9 (d, J= 176.4 Hz), 78.6, 71.6, 59.5, 37.5, 32.9; ¹⁹F NMR (282 MHz, Methylene Chloride-d₂) δ -68.41 (s), -156.54 (dddd, J = 57.7,

-71- 24.8, 16.4, 6.7 Hz); HRMS (ESI) m/z cal'd Ci₄HiiF₄NNaO [M+Na]⁺: 308.0674, found 308.0670.

[00143] Minor isomer: Ή NMR (500 MHz, Methylene Chloride-d₂) δ 7.63 - 7.59 (m, 1H), 7.52 - 7.48 (m, 2H), 7.38 - 7.34 (m, 1H), 6.07 - 6.01 (m, 1H), 5.97 - 5.94 (m, 1H), 4.22 - 4.13 (m, 1H), 3.99 - 3.92 (m, 1H), 3.05 - 2.97 (m, 1H), 2.71 - 2.60 (m, 1H), 2.32 (t, J = 2.5 Hz, 1H); ¹³C NMR (126 MHz, Methylene Chloride-ife) 5156.4, 141.1, 139.6, 130.5, 129.5, 125.8, 125.3, 115.6 (q, J= 287.5), 93.5 (d, J = 176.4 Hz), 78.7, 72.8, 58.1, 36.5, 33.5; ¹⁹F NMR (282 MHz, Methylene Chloride-d₂) 5 -69.5 -156.13.

[00144] Diastereomer 23b

(containing two geometrical isomers in 2.3:1 ratio due to the amide moiety) Major isomer: ^XH NMR (500 MHz, CDCls) 5 1.66 (dd, J = 23.9, 6.4 Hz, 3H), 2.32 (s, 3H), 5.64 (dq, J = 47.6, 6.4 Hz, 1H), 7.20 - 7.04 (m, 2H), 7.46 - 7.35 (m, 2H); ¹³C NMR (125 MHz, CDCI3) 5 21.5, 23.0, 90.5, 121.8, 126.5, 139.0, 150.6, 169.6; ¹⁹F NMR ¹⁹F NMR (282 MHz, Methylene Chloride-d₂) 5 -68.71 (s), -160.92 (ddd, J = 55.4, 30.9, 22.3 Hz); HRMS (ESI) m/z cal'd Ci₄Hi₂F₄NO [M+H]⁺: 286.0855, found 286.0858.

[00145] Minor isomer: ¹⁹F NMR (282 MHz, Methylene Chloride-d₂) -69.82, - 162.33.

[00146] Compound 24

. Purification by flash chromatography (hexanes to 15% EtOAc/hexanes). Ή NMR (300 MHz, Methylene Chloride-d₂) 5 7.87 - 7.74 (m, 3H), 7.48 (dt, J= 8.4, 1.1 Hz, 1H), 7.21 (dq, J = 5.3, 2.6 Hz, 2H), 6.09 (ddd, J = 46.9, 8.7, 4.0 Hz, 1H), 3.96 (s, 3H), 3.33 (ddd, J = 16.9, 14.7, 8.8 Hz, 1H), 2.96 (ddd, J = 32.0, 16.9, 4.0 Hz, 1H), 2.24 (s, 3H); ¹³C NMR (126 MHz, Methylene Chloride-d₂) 5 204.9, 158.7, 143.8, 135.2, 134.6, 130.0, 128.9, 127.8, 125.4, 124.3, 119.8, 106.1, 90.9 (d, J = 169.2 Hz), 55.8, 50.8, 31.1; ¹⁹F NMR (282 MHz, Methylene Chloride-d₂) 5 -171.62 (ddd, J=

-72- 47.1, 32.0, 14.7 Hz); HRMS (ESI) m/z cal'd Ci₅Hi₅FNa0₂ [M+Na]⁺: 269.0954, found.

[00147] Compound 25

. Purification by column chromatography (hexanes to 5% EtOAc/hexanes). ^XH NMR (500 MHz, CDC1₃) 1.34 (s, 3H), 1.37 (s, 12H), 2.39 - 2.06 (m, 2H), 2.65 (s, 3H), 6.44 (ddd, J = 53.9, 5.9, 1.5 Hz, 1H), 7.43 (t, J = 1.5 Hz, 1H), 7.77 (d, J = 1.7 Hz, 1H); ^C NMR (125 MHz, CDCI3) δ 28.6, 29.0, 31.4, 31.5, 35.2, 42.7, 48.4, 93.9, 123.6, 125.7, 134.8, 135.2, 154.2, 155.9, 199.9; ¹⁹F NMR -158.6 ppm; MS (EI) m/z cal'd C₁7H₂3FO [M]⁺: 262.2, found 262.2.

[00148] Compound

. Purification by flash chromatography (hexanes to 50% EtOAc/hexanes). Ή NMR (500 MHz, Methylene Chloride-d₂) δ 7.97 (d, J= 8.7 Hz, 2H), 7.58 (d, J= 8.7 Hz, 2H), 7.44 (dd, J = 8.2, 1.7 Hz, 2H), 7.39 - 7.30 (m, 2H), 6.88 (s, 1H), 5.45 (d, J = 47.4 Hz, 2H), 3.10 (s, 3H); ¹³C NMR (126 MHz, Methylene Chloride-d₂) δ 144.8 , 143.9 (q, J = 38.5 Hz), 143.2 , 140.2, 137.8 (d, J = 17.2 Hz), 129.1, 128.9, 128.6, 127.8, 125.7 , 121.2 (q, J= 268.9 Hz), 106.8, 83.9 (d, J= 166.7 Hz), 44.4; ¹⁹F NMR (282 MHz, Methylene Chloride-d₂) δ -62.81, -210.40 (t, J= 47.4 Hz); HRMS (ESI) m/z cal'd C18H16F4N2O2S [M+H]⁺: 39 .0785.

[00149] Compound 27

Purification by flash chromatography (hexanes to 50% EtOAc/hexanes). Ή NMR (500 MHz, acetone- de) δ 8.39 (d, J = 5.5 Hz, 1H), 7.69 (d, J= 5.5 Hz, 1H), 7.65 (s, 1H), 7.39 (s, 1H),

7.19 (d, J = 1.9 Hz, 1H), 7.11 (d, J = 47.6 Hz, 1H), 7.01 (dt, J= 8.3, 1.6 Hz, 1H),

6.96 (d, J = 8.3 Hz, 1H), 4.01 (s, 3H), 3.74 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H); ¹³C

NMR (126 MHz, acetone-de) δ 155.6, 155.4, 153.9, 151.29 , 150.5 , 150.3 , 141.3,

-73- 135.1, 132.5, 127.5, 122.8, 121.2, 119.8, 112.4, 111.1, 106.4, 104.5, 96.0 (d, J = 173.9 Hz), 56.3, 56.2, 56.1;¹⁹F NMR (282 MHz, acetone-de) δ -172.05 (d, J= 47.4 Hz); HRMS (ESI) m/z cal'd C10H21FNO4 [M+H]⁺: 358.1455, found 461.358.1463.

[00150] Compound 28

. Purification by flash chromatography (hexanes to 30% EtOAc/hexanes). Ή NMR (500 MHz, acetone- de) (~ 1.5:1 mixture of diastereomers with 6% unknown impurities) Ή NMR (500 MHz, Methylene Chloride-d₂) δ 7.35-7.45 (m, 5H), 5.86/5.48 (ddd, J= 49.4,

11.2, 1.7 Hz/J = 48.0, 9.7, 4.0 Hz, 1H), 5.00 - 4.80 (m, 2H), 4.44/4.34 (dd, J = 8.6, 4.1 Hz/J = 8.5, 4.2 Hz, 1H), 4.27 - 4.07 (m, 4H), 3.74 (m, 2H), 3.03/2.89 (m, 1H), 2.31 - 1.84 (m, 5H), 1.58 - 1.40 (m, 3H), 1.31 - 1.23 (m, 6H); ¹³C NMR (126 MHz, Methylene Chloride-d₂) δ 189.9, 171.5, 169.2 , 166.6, 156.2, 139.8/139.0, 128.9 , 128.7, 128.6, 128.3, 128.3, 126.1, 125.6/125.1, 124.3, 117.3, 115.0, 93.2(d, J = 170.3 Hz)/91.20 (d, J = 171.7 Hz), 61.7, 61.1, 59.9, 59.8, 54.5, 54.0, 46.6,

40.3, 36.8, 33.9, 32.3, 31.1, 28.9, 24.8, 17.0, 13.9; ¹⁹F NMR (282 MHz, Methylene Chloride-d₂) δ -69.09, -180.67 (ddd, J = 49.2, 40.8, 14.5 Hz)/ δ -68.81, -174.72 (ddd, J= 47.7, 34.1, 13.7 Hz); HRMS (ESI) m/z cal'd C24H₃oF4N₂Na06 [M+Na]⁺: 541.1938, found 541.1940.

[00151] Compound 29

Purification by flash chromatography (hexanes to 60% EtOAc/hexanes). Ή NMR (300 MHz, Methylene Chloride-d₂) δ 7.30 - 7.13 (m, 4H), 5.97 (s, 1H), 5.64 (ddd, J = 49.0, 10.0, 2.0 Hz, 1H), 4.49 - 4.26 (m, 4H), 2.71 - 2.49 (m, 3H), 2.33 (ddd, J = 17.3, 15.6, 10.0 Hz, 1H), 2.09 (s, 3H), 2.03 (s, 3H), 1.95 (s, 3H), 1.63 (m, 2H), 1.36 - 1.22 (m, 10H), 0.86 (t, J = 6.8 Hz, 1H); ¹³C NMR (126 MHz, Methylene Chloride-d₂) δ 171.4, 170.8, 144.1, 137.8, 129.0, 125.7, 92.0 (d, J = 168.3 Hz), 65.6, 64.4, 58.1, 53.9, 39.7, 36.1, 32.4, 32.0, 29.9, 29.8, 24.4, 23.2, 21.1, 14.4; ¹⁹F NMR (282 MHz, Methylene Chloride-d₂) δ -171.25 (ddd, J= 49.0, 42.1, 17.5 Hz); HRMS (ESI) m/z cal'd C₂₅H₃8FNNa0₅ [M+Na]⁺: 474.2632, found 474.2632.

-74- [00152] Compound 30

. Ή NMR (500 MHz, acetone-d₆) δ

7.38 - 7.27 (m, 3H), 6.38 (br, 1H), 5.60 (ddd, J= 47.6 7.6, 4.0 Hz, 1H), 3.58 - 3.44 (m, 2H), 2.29 (s, 3H), 2.28 (s, 3H), 1.43 (s, 9H). ¹³C NMR (126 MHz, acetone-d₆) δ 167.79, 167.78, 155.84, 142.65, 142.59, 136.60, 123.81, 123.70, 121.11, 91.96, 78.30, 45.94, 27.72, 19.67, 19.66; ¹⁹F NMR -182.20 ppm; MS (HR-ESI) m/z cal'd C17H23FNO6 [M+H]⁺: 356.1509, found 356.1510.

[00153] Compound

Purification by flash chromatography (hexanes to 10% EtOAc/hexanes). ^XH NMR (500 MHz, Methylene Chloride-^) (~ 2.8:1 mixture of diastereomers) δ 8.20 - 8.07 (m, 1H), 7.94 - 7.77 (m, 2H), 7.58 - 7.41 (m, 5H), 7.37 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 10.1 Hz, 2H), 6.17 (s, 1H), 5.10/4.67 (ddd, J= 47.9, 8.8, 3.8 Hz, 1H), 3.17 (s, 1H), 2.82 (ddd, J= 14.4, 9.7, 5.0 Hz, 1H), 1.77 (dtd, J= 20.0, 11.0, 10.3, 5.5 Hz, 1H), 1.61 (d, J = 6.9 Hz, 3H), 1.52 - 1.42 (m, 9H), 0.99 - 0.75 (m, 1H); ¹³C NMR (126 MHz, Methylene Chloride-d₂) δ 155.6, 141.5, 137.1, 134.3, 132.8, 129.5, 129.4, 129.3, 129.2, 129.1, 127.1, 126.4, 125.7, 125.3, 125.1, 125.0, 124.5, 122.2, 92.7 (d, J = 172.1 Hz), 80.4, 50.0, 39.2, 30.3, 28.8, 17.3; ¹⁹F NMR (282 MHz, Methylene Chloride-d₂) δ -62.96, -179.23/-181.13 ; HRMS (ESI) m/z cal'd C27H₂9F₄NNa02 [M+K]⁺: 498.2032, found 498.2032.

[00154] New compositions of matter including the compounds set forth above, which are fluorinated derivatives of known drug molecules, were prepared and utility was demonstrated for pharmaceutical applications. Due to the nature of fluorine substitution for hydrogen in a bio-active molecule, these compounds will likely also be active, perhaps even more so than the parent compounds.

[00155] Example 6 - Ibuprofen

-75- [00156] Ibuprofen is a widely used NSAID analgesic agent. It is known to cross the blood brain barrier and has shown promising results in reducing inflammation associated with Alzheimers disease.

[00157] Fluorinated ibuprofen was prepared and characterized and it was shown that it has anti-inflammatory activity. Fluorinating ibuprofen methyl ester was shown to work with ¹⁸F fluoride. ¹⁸F fluoro-ibuprofen was produced from this methyl ester precursor. The methyl ester can be hydrolyzed to form ¹⁸F fluoro-ibuprofen, which is the active form of the drug. ¹⁸F fluoro-ibuprofen was made by basic hydrolysis (LiOH) of ¹⁸F fluoro-ibuprofen methyl ester.

[00158] Enzyme inhibition studies have shown that the fluorinated derivatives have equal or greater inhibition of prostaglandin synthases (COX 1 and COX 2) than the parent drug.

[00159] The activity found, that fluoro-ibuprofen binds COX enzymes, indicates that 18F fluoro-ibuprofen may illuminate the locations of COX enzymes in the brain. Methods described herein may include ¹⁸F fluoro- ibuprofen in drug development or in diagnostic methods utilizing positron emission tomographic imaging (PET scanning). This property could be used to detect areas of inflammation in the brain associated with such disorders as Alzheimer's disease.

[00160] Direct fluorination of ibuprofen methyl ester was described above and reported by us in International Patent Application Nos. PCT/US2012/051628, filed August 20, 2012; and PCT/2012/051617, filed August 20, 2012, both of which are incorporated herein by reference as if fully set forth. A two-step fluorination of ibuprofen methyl ester has also been reported: Chemo-enzymatic fluorination of unactivated organic compounds Andrea Rentmeister, Frances H Arnold & Rudi Fasan, Nature Chemical Biology 5, 26 - 28 (2009), which is incorporated herein by reference as if fully set forth. But the two-step method is not a direct fluorination as reported herein.

[00161] Fluorinated derivatives of ibuprofen, as set forth above, and at least nine other molecules (rasagiline, nabumetone, celestolide, celecoxib analog, papaverine, protected enalaprilat, fingolimod, protected dopamine and

-76- N-boc-cinacalcet) have not been described in the literature before. See FIG. 3. These compounds are prepared and characterized herein and may be part of any embodiment herein. As expected, F-ibuprofen has anti-inflammatory activity. From these results it was concluded that ¹⁸F fluorinated drug molecules from various protected precursors could be made by the methods herein. Further, the protecting groups may hydrolyze spontaneously in vivo to form, for example, ¹⁸F fluoro-ibuprofen, which is the active form of the drug. Similar transformations are expected for the other derivatives.

[00162] Example 7 - computational details

[00163] All calculations were carried out with Gaussian 03, Revision E.01, except for orbital diagrams, which were quasi-restricted orbitals generated by ORCA 2.8. (Frisch, M. J. et al., Gaussian 03 (Revision E.01), Gaussian Inc., Wallingford, CT, 2004; Neese, F. Journal of the American Chemical Society 2006, 128, 10213; which are incorporated by reference herein as if fully set forth).

[00164] Geometry optimizations were fully optimized at b31yp/6-3lG(d) (SDD for Mn) level of theory without symmetry constraints. The nature of all stationary points was confirmed by frequency analysis at the same level of theory as in geometry optimization. The zero-point vibrational energies (ZPVE) and the thermal correction to Gibbs free energies (TCGE) obtained from the frequency analysis were used for further correction of the single-point energies (SPE). Single-point energies were calculated with a larger basis set (SDD for Mn and 6-311++G(2df, 2p) for C, H, N, O and F). The final free energies of each species (G) were obtained using the following equation. G = SPE + TCG - 0.0194ZPVE. The solvation energies of each species were calculated with CPCM solvation model at b31yp/6-311++G(2df, 2p) (SDD for Mn) level of theory using uaks radii. The reference state of all calculation is 1 atm and 298 K for gas- phase and 1 mol/L and 298 K for solution-phase.

-77-

Loosely bound pre-coordination complex

Charge = 0, spin multiplicity = 5

Mn 3.19157000 12.48346400 2.67574800

O 3.06663000 12.42527000 0.80470700

O 5.06334900 12.36527900 2.77158300

N 1.20300900 12.51373600 2.84243800

N 3.08458600 12.66242500 4.67959400

C 2.10774100 11.85533800 0.11506000

C 2.37986600 11.45711800 -1.21677300

C 1.38953100 10.90657000 -2.01138200

C 0.07805800 10.72865000 -1.52803200

C -0.21443100 11.11625300 -0.23509200

C 0.77589000 11.67233600 0.60900900

C 0.39708500 12.08305100 1.92931100

C 0.75095300 12.95576400 4.15866100

C 1.74338700 12.39470200 5.18757000

C 5.39490700 13.32592700 4.97262500

C 6.31215000 13.90549300 5.87915800

C 7.62241400 14.15554000 5.51691200

C 8.04540400 13.81175300 4.21943300

C 7.17535400 13.23233000 3.31047600

C 5.82937100 12.97172300 3.65627700

H 3.38931200 11.60272500 -1.58732600

H 1.63118400 10.60650500 -3.02812000

H -0.68864500 10.29570000 -2.16261200

H -1.22158800 10.99320100 0.15777000

H -0.66922300 12.03597000 2.17172800

H 0.76806200 14.05166300 4.18190100

H -0.27049300 12.61117600 4.36197700

H 1.61695700 11.30902300 5.26534400

H 1.59322800 12.84731800 6.17570500

H 3.85115600 13.24585900 6.48613600

H 5.96334300 14.16126700 6.87766400

H 8.31348100 14.60943400 6.21996500

H 9.07291800 14.00431500 3.92094400

H 7.49771500 12.96332100 2.30989000

C 4.05314300 13.07530700 5.42316000

F 3.22804900 14.30722200 2.65487900

O 3.03168500 10.66583200 2.82901600

H 3.94209200 10.32356200 2.79456800

-78- C 1.15575400 16.79118500 3.68136200

H 0.94739900 17.39590000 4.55947300

H 2.11455100 16.28788600 3.61263900

C 0.21793400 16.68894000 2.63447600

C 0.50848800 15.91543600 1.46815500

C -1.04807300 17.34493600 2.69186200

C -0.41483900 15.81063900 0.43805500

H 1.46867700 15.41025600 1.41063300

C -1.96075600 17.23069400 1.65396800

H -1.28907600 17.94364300 3.56749600

C -1.65477000 16.46331200 0.51976300

H -0.17147400 15.21876100 -0.44090500

H -2.91830300 17.74181300 1.71899600

H

Charge = 0, spin multiplicity = 5

Mn 2.74191200 12.24432700 2.32336500

O 3.14658300 11.90530400 0.51235300

O 4.53470600 12.61938800 2.90469600

N 0.77317000 11.95247300 1.96890100

N 2.04919900 12.72260600 4.15268200

C 2.48556900 11.11008800 -0.29010500

C 3.14901200 10.61102300 -1.44009300

C 2.49526200 9.79917400 -2.34941900

C 1.14369000 9.44241700 -2.17153600

C 0.47022100 9.92303300 -1.06597500

C 1.10803700 10.75048000 -0.11099100

C 0.32689200 11.24105000 0.98793600

C -0.07776600 12.44436800 3.04595200

C 0.68842700 12.23719300 4.36155000

C 4.03927300 13.88219400 4.91151000

C 4.53837100 14.75645300 5.90623300

C 5.82866900 15.24876700 5.85591200

C 6.66360300 14.85236900 4.79214700

C 6.21290900 13.98865000 3.80963000

C 4.89159500 13.46974100 3.83274200

H 4.18964400 10.88843700 -1.57431300

H 3.03804900 9.42873400 -3.21590900

H 0.64240800 8.80278800 -2.89108800

H -0.57553300 9.66465500 -0.91004500

H -0.74116500 10.99466400 0.97488200

-79- -0.25348000 13.51596100 2.89089000 -1.04484400 11.92454800 3.06486300 0.74272900 11.16602900 4.58473600 0.20015300 12.75968800 5.19410000 2.16602400 13.66405000 5.96744500 3.87707000 15.04227500 6.72235500 6.19506000 15.92299400 6.62365400 7.68252300 15.22906500 4.74135600 6.85606200 13.67490200 2.99346800 2.68695000 13.41142400 5.03726900 2.49299300 14.14201000 1.91590200 2.81123000 10.42165600 2.82337300 3.72832500 10.24985400 3.09664800 2.57887100 16.11037400 1.55481200 3.61701900 16.14209800 1.85954900 2.38707700 15.94810500 0.50183900 1.57989400 16.70309600 2.37720500 0.25034000 16.86761000 1.90944200 1.87838700 17.12337900 3.69931800 -0.72615000 17.42993800 2.72138500 0.00554900 16.54873800 0.89926000 0.89628700 17.68593900 4.50479100 2.89001300 16.99582200 4.07589100 -0.41008700 17.84309500 4.02281100 -1.73768100 17.55471200 2.34368100 1.14398500 18.00969300 5.51250500 -1.17449700 18.28751000 4.65423400

Charge = 0, spin multiplicity = 5

3.36239800 11.48183800 2.88830300

3 .40837400 11.02243400 1.06549100

4 .78239600 12.79074000 2.74604100

1 .23467700 12.03008200 2.62476900

2 .89608400 12.30143300 4.68319500

2, .44322100 10.77012000 0.20126700

2, .81581000 10.20219700 -1.04169300

1. .87611600 9.90910900 ^■ -2.01606500

0, .50981100 10.15980500 -1.80089600

0, .11925300 10.71263400 -0.59498300

1. .05025600 11.03653500 0.41924400

0, .52370400 11.61409100 1.63698300

0, .63253400 12.51946800 3.85658700

1. .50392000 12.02416100 5.03272900

4, .91846200 13.60014700 5.02126700

5, .65832400 14.34996200 5.96858900

-80- C 6.86776600 14.92787000 5.64114900

C 7.35754000 14.78089700 4.32629900

C 6.65254800 14.07227400 3.37097900

C 5.41719600 13.44654300 3.68349600

H 3.87211600 10.00898000 -1.20075000

H 2.20389200 9.47492800 -2.95752900

H -0.22401300 9.92309700 -2.56491600

H -0.93374800 10.91488100 -0.40781400

H -0.57226700 11.68012500 1.69487700

H 0.64633900 13.61822600 3.84699700

H -0.40902800 12.18831900 3.97743800

H 1.39119200 10.94200500 5.14640400

H 1.21821700 12.52622500 5.96637000

H 3.22947100 13.44241500 6.35567900

H 5.25293900 14.46061200 6.97260100

H 7.43008500 15.49223100 6.37824300

H 8.30666400 15.23722300 4.05529400

H 7.02399700 13.96300800 2.35698900

C 3.63169500 13.09528800 5.39674100

O 3.00039600 9.80124500 3.54928000

H 2.98720 .15190300 2.82748600

Charge = 0, spin multiplicity = 1

C 1.85857900 1.01056300 -0.05412400

C 0.49536600 1.30288100 -0.01790400

C -0.44928500 0.27222200 0.04954700

C -0.01334900 -1.05544700 0.07199500

C 1.35092500 -1.34776800 0.02852800

C 2.29031200 -0.31754500 -0.03161600

H 2.58280500 1.81915400 -0.10791800

H 0.16506500 2.33975800 -0.04527900

H -0.74723700 -1.85329600 0.11292400

H 1.67958500 -2.38374000 0.04104200

H 3.35204900 -0.54660100 -0.06521600

C -1.92016200 0.60241100 0.13619900

H -2.19276600 0.91774100 1.15298700

H -2.18039700 1.41713100 -0.55176600

F -2.70371300 -0.50156100 -0.18139200

[00165] Example 8 - direct labeling of unactivated aliphatic C-H bonds with [¹⁸F]fluoride in the presence of manganese porphyrin complexes

[00166] Despite success of the direct C_sp ³-H bond ¹⁸F labeling with no- carrier-added [¹⁸F] fluoride, this method is limited to labeling benzylic positions

-81- while benzylic fluoride unit is not particular common in pharmaceuticals and radiopharmaceuticals. Given this limitation, a general method was developed that can directly label unactivated aliphatic C-H bonds with [¹⁸F]fluoride. Incorporation of ¹⁸F at these positions may increase the metabolic stability of the target molecules, as the labeling positions are likely the sites of phase I metabolism by cytochrome P450 enzymes. In this context, a manganese porphyrin mediated ¹⁸F labeling strategy was developed that can selectively replace an unactivated aliphatic sp³ hydrogen with ¹⁸F atom, which can be used for the synthesis of labeled molecules suitable for PET imaging.

[00167] After extensive screening, it was found that in the presence of a manganese porphyrin coordinated with a tosyl ligand, Mn(TPFPP)OTs, in conjunction with a terminal oxidant iodosylbenzene, a protected five-membered non-natural amino acid derivative, 1-amino-cyclopentanecarboxylic acid (Boc- ACPC-OMe) can be efficiently labeled with ¹⁸F exclusively at the C3 position. As briefly illustrated in Table 2, various tosyl coordinated manganese porphyrins and salen complex were evaluated. Employment the manganese salen complex, which effects benzylic C-H ¹⁸F labeling, afforded only trace amount of aliphatic labeling product (Huang, X. Y.; Liu, W.; Ren, H.; Neelamegam, R.; Hooker, J. M.; Groves, J. T. J. Am. Chem. Soc. 2014, 136, 6842, which is incorporated herein by reference as if fully set forth). The rationale is that the intermediate 0=Mn^v(salen) species is not reactive enough to effectively abstract strong aliphatic C-H bonds.

[00168] Different manganese porphyrin complexes were evaluated, as they have been shown to be efficient catalysts for aliphatic C-H halogenations (Liu, W.; Huang, X. Y.; Cheng, M. J.; Nielsen, R. J.; Goddard, W. A.; Groves, J. T. Science 2012, 337, 1322; Liu, W.; Groves, J. T. J. Am. Chem. Soc. 2010, 132, 12847, both of which are incorporated herein by reference as if fully set forth). Although Mn(TMP)OTs only afforded moderate radiochemical conversion, introducing electron-withdrawing meso-substituents into the porphyrin ring significant increases the labeling efficiency, with Mn(TPFPP)OTs affording a RCC of 32%. After optimizing of the solvent and oxidant loading, it was found

-82- that protected 3-[¹⁸F]-FACPC can be achieved in an acetone/acetonitrile solution with a radiochemical conversion up to 48% within only 10 minutes.

[00169] Table 2. Reaction optimizations of direct aliphatic C-H 18F fluorination

NHBoc

COOMe

50°C

[Mn] Solvents PhlO RCC%

1 Acetone 1.1 eq. trace

2 Acetone 1.1 eq. 6

3 Acetone 1.1 eq. 24

4 Acetone 1.1 eq. 31

5 Acetone 1.1 eq. 32

5 CHsCN 1.1 eq. 36

5 CH₃CN/Acetone 2:1 1.1 eq. 38

5 CH₃CN/Acetone 2:1 1.7 eq. 48

[00170] With the optimized conditions in hand, the substrate scope of this direct aliphatic ¹⁸F labeling reaction was further investigated. As displayed in Scheme 2, a variety of simple molecules bearing multiple unactivated C_sp ³— H bonds were efficiently labeled with radio chemical conversion ranging from 12% to 67%.

[00171] Scheme 2. Substrate scope of the Mn-mediated aliphatic C-H ¹⁸F fluorination

-83-

49% ± 10% (n=3) 37 ± 6% (n=4) Tandospirone

[00172] Common functional groups including amide, ketone, ester, imide, sulfonamide, nitrile, halogens, alcohol and cyanide are well tolerated under the standard reaction conditions. The labeling usually occurs at the least sterically hindered and most electron rich methylene or methine positions. For example, labeling of a series of substituted butyl benzoates occurs predominantly at the methylene positions remote from the electron- withdrawing benzoate group. In addition, substituted five-member ring compounds afforded C3 labeled fluoride as the major products, probably due to the stereoelectronic effect. Notably, labeling of phenylcyclohexanol results the ¹⁸F incorporation exclusively at the positions cis to the hydroxyl group, indicating the involvement of a directive

-84- effect in the fluorine transfer step. Such a directive effect has also been observed in Mn-¹⁹F fluorination reaction and is probably due to the hydrogen bonding of the OH group with the F-Mn^IV(por) intermediate through a six- member transition state. Indeed, such a directive effect has never been observed in other metalloporphyrin mediated C-H functionalization reactions. Moreover, this labeling protocol can be used to prepare radiolabeled drug precursors, which can then be converted to the ¹⁸F labeled drug analog. For example, [¹⁸F]-fluoro-tandospirone, a potential 5-HT imaging agent, can be prepared via a two-step protocol in an overall 30 % RCC (Endo, S. Cns Drugs 1996, 5, 154, which is incorporated by reference herein as if fully set forth).

[00173] Example 9 - ¹⁸F labeling of bioactive molecules mediated by manganese porphyrin complexes

[00174] In order to demonstrate the utility of this method for late- stage radiolabeling, the system was applied to a variety of bioactive molecules. ¹⁸F- labeled imaging that target the increased rates of amino acid transport by many tumor cells (Gao, Z. et al., Angew. Chem. Int. Ed. 2012, 51, 6733, which is incorporated herein by reference as if fully set forth). A direct fluorination method could significantly accelerate the development of amino acid based PET tracers. Scheme 3 illustrates direct rdioactive labeling of a variety of bioactive molecules. Although direct fluorination of leucine and valine have recently been achieved using electrophilic fluorine source, Selectfluor or NFSI, direct ¹⁸F labeled leucine or valine analogs have never been reported, probably due to the synthetic inaccessibility. Referring to Scheme 3, subjection of the protected analogues of these two amino acids to standard labeling conditions described herein affords exclusively tertiary-labeled compounds with RCCs of 29% and 31%, respectively. The tertiar selectivity has also been observed in the labeling a leucine containing dipeptide complex, Boc-Val-Leu-OMe. In addition, ¹⁸F labeled tyrosine analogues, such as 2-[(¹⁸)F]-fluoro-L-tyrosine (FTYR) and O-(2'- [¹⁸F]fluoroethyl)-L- tyrosine (FET), are also promising tracers for brain imaging

-85- (Wang, L. M. et al., Bioorg. Med. Chem. Lett. 2010, 20, 3482, which is incorporated herein by reference as if fully set forth).

[00175] Referring to Scheme 3, under standard labeling reaction described herein, a cyclopentane carboxylic ester derivative of tyrosine affords the aliphatic ring labeling with RCC of 40%. These compounds could be potential tracers for amino acid transporter imaging.

[00176] Scheme 3. Selective raidofluorination of bioactive molecules.

SF-ACPC (protected) ¹⁸F-Leucine (protected) ^SF-Va!ine (protected) Amino acid transporter Amino acid transporter Amino acid transporter

48% ± 5% (n=10) 29% ± 4% (n=3) 31 % ± 3% (n=3)

¹⁸F-Valine-Leucine (protected) ⁸F-Tyrosine derivative ^:-Lyrica (protectee

Dipeptide Amino acid transporter anticonvulsant

37% ± 5% (n=3) 40% ± 6% (n=3) 22 ± 7% (n=3)

sF-N-Boc-Amantadine ¹⁸F-Ezetimibe analog ^aF-FSutamide analog

antiparkison lowering cholesterol prostate cancer

19 ± 8% (n=3) 31 ± 5% (n=3) 32 % ± 8% (n=3)

[00177] Another important application of PET imaging is in the area of pharmacokinetic as a noninvasive method for determining drug distribution and action (Fischman, A. J.; Alpert, N. M.; Rubin, R. H. Clin Pharmacokinet

2002, 41, 581, which is incorporated by reference herein as if fully set forth).

[00178] Thus, an efficient method for introducing ¹⁸F on a pre-existing drug motif may prove very useful in medicinal chemistry. In this context, a few important drug molecules have been subjected to standard labeling conditions described herein. Radiolabeling of pregabalin, an anticonvulsant drug that has

-86- been commercialized by Pfizer under the trade name LYRICA^®, afforded mainly tertiary-labeled product Dworkin, R. H.; Kirkpatrick, P. Nat Rev Drug Discov 2005, 4, 45, which is incorporated by reference herein as if fully set forth). Analogues of flutamide, a prostate cancer drug, and ezetimide, a cholesterol lowering drug, can both be efficiently labeled at the tertiary positions with RCCs of 32% and 31% respectively (Baker, J. W.; Bachman, G. L.; Schumach.I; Roman, D. P.; Tharp, A. L. J. Med. Chem. 1967, 10, 93, which is incorporated by reference herein as if fully set forth).

[00179] Radio-fluorination of amantadine, an antiviral and antiparkison drug, afforded a mixture of tertiary and secondary labeled compounds, which can be easily separated on HPLC. The separation of these regioisomers offers the potential for rapid test of imaging properties of labeled analogues from a single late-stage synthetic product.

[00180] Furthermore, this method was successfully translated into a reliable and reproducible way that can afford radiolabeled molecules on a scale suitable for animal studies. The scale up of the labeling reaction was achieved by using a "dry-down free" protocol. Namely, [¹⁸F] fluoride captured on an anion exchange cartridge is eluted using an acetone/acetonitrile solution of Mn(TPFPP)OTs, with over 90% elution efficiency of the ¹⁸F fluoride. Synthesis of the protected 3-[¹⁸F]-FACPC was accomplished within 10 min using the eluted Mn(TPFPP)¹⁸F solution in conjunction with terminal oxidant, PhlO. One concern one may have regarding to the C-H radiofluorination is the separation of labeled products from the C-H precursors (Brooks, A. F.; Topczewski, J. J.; Ichiishi, N.; Sanford, M. S.; Scott, P. J. H. Chemical Science 2014, 5, 4545, which is incorporated by reference as if fully set forth).

[00181] Indeed, it was found that protected 3-[¹⁸F]-FACPC (retention time = 9 min) can be easily separated from the precursor (retention time = 15 min) using a reverse phase semi-prep HPLC column. After deprotection with 6N HC1 at 120°C for 10 min, the final 3-[¹⁸F]-FACPC is captured with a solid phase extraction column and formulated in a sterile saline solution. Starting with an approximately 400 mCi of radioacitivty, this method can be used to produce >5

-87- mCi of formulated 3-[¹⁸F]-FACPC within 60min. A direct aliphatic C-H ¹⁸F labeling method using non-carrier-added [¹⁸F]fluoride. The value of this transformation has been highlighted via the radiofluorination of biologically active molecules without the need for pre-activation.

[00182] Represenative, non-limiting Materials

[00183] Manganese tetrakis(pentafluorophenyl)porphyrin chloride (Mn(TFPP)Cl) was prepared by refluxing the free base with manganese acetate, followed by HCl treatment as previous reported. Mn(TPFPP)OTs was prepared by treating Mn(TPFPP)Cl with stoichiometric amounts of silver tosylate in refluxing toluene. Iodosylbenzene (PhIO) was prepared by hydrolysis of iodobenzene diacetate with sodium hydroxide solution. Other purchased materials were of the highest purity available from Aldrich and used without further purification. ^XH NMR spectra were obtained on a Bruker NB 300 spectrometer or a Bruker Avance-III (500 MHz) spectrometer and are reported in ppm using solvent as an internal standard (CDCI3 at δ 7.26, acetone-cfe at 2.04, or methylene chloride-cfe at 5.32). Data reported as: chemical shift (δ), multiplicity (s= singlet, d = doublet, t = triplet, q = quartet, m = multiple t), coupling constant (Hz); integrated intensity. ¹³C NMR spectra were recorded on a Bruker 500 (125 MHz) spectrometer and are reported in ppm using solvents as an internal standard (CDCI3 at 77.15 ppm, acetone-d6 at 29.92 ppm, or methylene chloride-cfe at 54.0). ¹⁹F NMR spectra (282 MHz) were obtained on a Bruker NB 300 spectrometer and were referenced relative to relative to CFCI3. GC/MS analyses were performed on an Agilent 7890A gas chromatograph equipped with an Agilent 5975 mass selective detector. High-resolution mass spectra were obtained from the Princeton University mass spectrometer facility by electrospray ionization (ESI). High-performance liquid chromatography (HPLC) was performed on an Agilent 1100 series instrument with a binary pump and a diode array detector.

[00184] Radiochemistry

[00185] No-carrier-added [¹⁸F]fluoride was produced from water 97% enriched in ¹⁸O (ISOFLEX, USA) by the nuclear reaction ¹⁸O(p,n)¹⁸F using a

-88- Siemens Eclipse HP cyclotron and a silver-bodied target at Massachusetts General Hospital Athinoula A. Martinos Center for Biomedical Imaging. The produced [¹⁸F] fluoride in water was transferred from the cyclotron target by helium push.

[00186] Example 10 - radiosynthesis of ¹⁸F labeled molecules mediated by Mn(TPFPP)OTs

[00187] A 4 mL vial with a screw cap was charged with Mn(TPFPP)OTs (16 mg, 0.022 mmol), substrate (0.25 mmol) and a stir bar (2 5 mm). A portion of aqueous [¹⁸F] fluoride solution (40 - 50

4 - 5 mCi) obtained from the cyclotron was loaded on to an Chromafix PS-HCO3 IEX cartridge, which had been previously washed with 5.0 mg/mL K2CO3 in Milli-Q water followed by 5 mL of Milli-Q water. Then, the cartridge loaded with [¹⁸F]fluoride was washed with 2 mL Milli-Q water and [¹⁸F]fluoride was released from the cartridge using 0.8 mL 5.0 mg/mL K2CO3 in Milli-Q water. A portion of the resulting [¹⁸F]fluoride solution (25

125 - 150 μϋί) was diluted with 3.0 mL acetone. 0.6 mL of this [¹⁸F]fluoride acetone solution was added to the vial containing the catalyst and the substrate. The resulting solution was stirred for 1 min at room temperature. Then 80 mg (0.25 mmol) iodosylbenzene (PhIO) was added to the solution, and the vial was capped and stirred at 50 °C for 10 min. After 10 min, an aliquot of the reaction mixture was taken and spotted on a silica gel TLC plate. The plate was developed in an appropriate eluent and scanned with a Bioscan AR-2000 Radio TLC Imaging Scanner.

[00188] Example 11 - radio-HPLC characterization of the ¹⁸F labeled products of Compounds 32 - 61

[00189] All ¹⁸F-labeled molecules were characterized by comparing the radio-HPLC trace of the crude reaction mixture to the HPLC UV trace of the authentic reference sample with methods detailed as follows. HPLC column: Agilent Eclipse XDB-C18, 5 μπι, 4.6 x 150 mm. Gradient: H₂0 (0.1% TFA, A) and ACN (0.1% TFA, B), 5% B - 95% B, 20 min, 1.0 ml/min. FIGS. 38 - 56

-89- illustrate comparison of the radio-HPLC trace of the crude reaction mixture to the HPLC UV trace of the authentic reference sample of Compounds 32 - 35, 37, 39 - 47, 50 - 51, and 53 - 55.

[00190] FIG. 57 illustrates Compound 59

[00191] FIG. 58 illustrates Compound 60

[00192] FIG. 59 illusrates Compound 61 -'

[00193] Example 12 - preparation and characterization of ¹⁹F authentic samples of Compounds 32 - 58

[00194] All of the ¹⁹F authentic compounds were prepared according to the previously reported direct C-H fluorination procedure.

F

ΥΛ ^ NHBOC

[00195] Compound 32 ^OOMe _e Synthesized according to published procedure. ^XH NMR (300 MHz, CDC1₃) δ 5.13 (d, J = 53.8 Hz, 1H), 5.00 (d, J = 56.5 Hz, 1H), 3.74 (s, 3H), 2.80 - 1.83 (m, 6H), 1.43 (s, 9H). ¹³C NMR (126 MHz, CDCI3) δ 174.24, 155.18, 95.50, 80.08, 65.26, 52.70, 44.62, 35.58, 32.81, 28.41; ¹⁹F NMR (282 MHz, CDCI3) δ 167.9 (major), 170.9 (minor) HRMS (ESI) m/z cal'd Ci₂H₂oFNNa +Na]⁺: 284.1274, found 284.1290.

[00196] Compound 33

. Synthesized according to published procedure, contaminated with -5% DCU. Ή NMR (300 MHz, CDCI3) δ 6.85 (s, 1H), 4.98 (s, 1H), 4.63 (ddd, J = 8.4, 7.1, 5.0 Hz, 1H), 4.14 (dq, J = 18.2, 7.1 Hz, 1H), 3.72 (s, 3H), 2.25 - 1.52 (m, 2H), 1.44 (s, 9H) 1.42 (s, 3H), 1.38 - 1.33(m, 6H). ¹³C NMR (126 MHz, CDCI3) δ 172.51, 172.37, 155.33, 95.82, 94.48, 52.52, 49.64, 41.97, 41.79, 28.20, 27.36, 26.03, 17.97; ¹⁹F NMR (282 MHz, CDCI3) δ 136.3 HRMS (ESI) m/z cal'd Ci5H₂7FN₂Na05 [M+Na]⁺: 357.1802, found 357.1810.

-90- [00197] Compound 34

. Synthesized according published procedure. Ή NMR (500 MHz, CDC1₃) δ 8.29 (tt, J= 1.6, 0.7 Hz, 1H), 8.26 - 8.19 (m, 1H), 7.85 - 7.79 (m, 1H), 7.59 (tt, J= 7.7, 0.8 Hz, 1H), 4.98 - 4.78 (m, 1H), 4.58 - 4.44 (m, 2H), 2.19 - 1.93 (m, 2H), 1.42 (dd, J= 23.9, 6.2 Hz, 3H). ¹³C NMR (126 MHz, CDCI3) δ 165.38, 132.94, 131.11, 129.68, 129.20, 126.70, 124.92, 122.77, 87.87 (d, J = 160 Hz), 61.88, 36.18, 21.35. ¹⁹F NMR (282 MHz, CDCI3) δ 175.75; MS (EI) m/z cal'd C12H12F4O2 [M]⁺264.1, found 264.1.

[00198] Compound 35 Me

. Synthesized according published procedure. Ή NMR (500 MHz, CDCI3) δ 4.96 - 4.76 (m, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 2.27 - 1.85 (m, 6H), 1.56 - 1.48 (m, 2H); ¹³C NMR (126 MHz, CDCI3) δ 173.91, 172.19, 95.14 (d, J = 189 Hz), 57.37, 52.00, 50.26, 42.14, 39.93, 32.09, 31.60, 27.65. ¹⁹F NMR (282 MHz, CDCI3) δ 164.02 (major), 157.77 (mionr). MS (EI) m/z cal'd C11H15FO4 [M]⁺230.1, found 230.1

[00199] Compound 36

. Synthesized according published procedure. Ή NMR (300 MHz, Acetone-de) δ 8.04 - 7.86 (m, 2H), 7.64 - 7.39 (m, 3H), 4.92 - 4.82 (m, 1H), 3.71 (s, 3H), 2.43 - 2.17 (m, 2H), 1.45 (dd, J= 21.3, 7.3 Hz, 6H), (N-H signal not observed). ¹³C NMR (126 MHz, CDCI3) δ 172.41, 165.95, 134.26, 131.42, 128.29, 127.20, 94.42 (d, J=173 Hz), 51.53, 49.52, 41.67, 26.33, 25.96; ¹⁹F NMR (282 MHz, CDCI3) 136.77; HRMS (ESI) m/z cal'd Ci4Hi₈FNNa0₃ [M+Na]⁺ 29 .1163.

[00200] Compound 37

Synthesized according published procedure. ^XH NMR (500 MHz, CDCI3) δ 5.16 (ddt, J= 53, 8.8, 1.6 Hz, 1H), 3.70

(s, 3H), 3.66 (s, 3H), 2.34 - 1.61 (m, 10H); ¹³C NMR (126 MHz, CDCI3) δ 176.48,

-91- 175.20, 90.66 (d, J = 155 Hz), 52.15, 51.99, 27.75, 27.33, 26.72, 26.07, 26.02, 20.31, 20.27; ¹⁹F NMR (282 MHz, CDC1₃) δ 173.17; MS (EI) m/z cal'd C12H17FO4 [M]⁺ 243.1, found 243.1

[00201] Compound 38

. Synthesized according published procedure. ^XH NMR (500 MHz, CDCI3) δ 5.16 (br, IH), 4.43 (t, J = 6.9 Hz, IH), 3.77 (s, 3H), 2.25 - 1.92 (m, 3H), 1.57 (d, J= 9.2 Hz, IH), 1.41 (s, 5H), 0.96 (ddt, J= 31.5, 16.3, 7.1 Hz, IH). ¹³C NMR (126 MHz, CDCI3) δ 173.38, 155.49, 95.26 (d, J=179.5 Hz), 80.28, 52.67, 51.06, 42.84, 28.55, 27.43, 26.78; ¹⁹F NMR (282 MHz, CDCI3) δ -136.62; HRMS (ESI) m/z cal'd Ci₂H₂2FNNa0₄ [M+Na]⁺ 286.1431, found 286.1420

[00202] Compound

δ

8.27 (s, IH), 8.23 (d, J= 8.0 Hz, IH), 7.84 (d, J= 8.0 Hz, IH), 7.58 (t, J= 7.8 Hz, IH), 5.59 (tdd, J = 6.4, 3.7, 2.4 Hz, IH), 5.23 (dt, J= 54.0, 4.8 Hz, IH), 2.51 (dddt, J= 26.6, 15.9, 6.8, 1.8 Hz, IH), 2.33 - 1.92 (m, 5H); ¹³C NMR (126 MHz, CDC1₃) δ 164.37, 136.21, 133.85, 133.41, 131.84, 129.68, 118.12, 113.17, 95.18 (d, J= 172 Hz), 77.08, 41.11, 31.55, 30.63; ¹⁹F NMR (282 MHz, CDC1₃) δ -171.44; MS (EI) m/z cal'd Ci₃Hi₂FN0₂ [M+Na]⁺ 233.1, found 233.1;

[00203] Compound

. Ή NMR (501 MHz, Chloroform-cT) δ 8.79 (s, IH), 8.41 (d, J = 8.1 Hz, IH), 8.34 (d, J = 7.7 Hz, IH), 7.65 (t, J = 8.0 Hz, IH), 5.61 (m, IH), 5.31 (d, J= 52.1, IH), 2.76 - 1.64 (m, 6H); ¹³C NMR (126 MHz, CDCI3) δ 164.06, 148.25, 135.28, 132.09, 129.65, 127.44, 124.44, 95.37, (d, j =168 Hz), 40.86, 32.78, 31.82, 30.40; ¹⁹F NMR (282 MHz, CDCI3) δ -171.47; MS (EI) m/z cal'd C12H12FNO4 [M]⁺ 253.1, found 253.1;

-92- [00204] Compound 41

Mi NMR (501 MHz,

CDCls) δ 7.14 - 6.99 (m, 4H), 6.88 - 6.75 (m, 1H), 5.25 (dt, J = 52.9, 3.4, 1H), 4.86 (dt, J = 7.6, 5.6 Hz, 1H), 3.78 (s, 3H), 3.44 - 3.23 (m, 1H), 3.23 - 3.12 (m, 2H), 2.49 - 1.85 (m, 6H); ¹³C NMR (126 MHz, CDCI3) δ 174.28, 170.24, 156.57, 150.16, 132.18, 130.19, 121.84, 115.53 (q, J = 287.7), 96.20 (d, J = 172 Hz), 53.52, 52.95, 41.71, 37.44, 36.63, 32.85, 27.46; ¹⁹F NMR (282 MHz, CDCI3) δ - 75.91 (-CF₃), -171.04 (-F); HRMS (ESI) m/z cal'd C18H20F4NO5 [M+H]⁺ 406.1278, found 406.1271;

NHBoc

[00205] Compound 42 - . ⁱR NMR (501 MHz, CDCI3) δ 4.46 (br, 1H), 2.33 (s, 2H), 2.10 (d, J = 5.9 Hz, 2H), 1.91 - 1.73 (m, 8H), 1.54 (d, J = 3.7 Hz, 2H), 1.43 (s, 9H); ¹³C NMR (126 MHz, CDCI3) δ154.02, 92.54 (d, J = 185 Hz), 79.08, 53.67, 46.78, 41.66, 40.45, 34.72, 30.95, 28.45; ¹⁹F NMR (282 MHz, CDCI3) δ -132.67 HRMS (ESI) m/z cal'd Ci₅H₂4FNNa0₂ [M+Na]⁺ 292.1689, found 292.1678;

[00206] Compound 43

Synthesized according published procedure, contaminated with non-fluorinated precursor. Ή NMR (501 MHz, CDCI3) δ 8.17 (m, 1H), 7.97 (ddd, J = 7.8, 1.6, 1.1 Hz, 1H), 7.68 (m, 1H), 7.32 (td, J = 7.9, 3.1 Hz, 1H), 4.87 (dm, J = 49.7 Hz, 1H), 4.53 - 4.39 (m, 2H), 2.18 - 1.92 (m, 2H), 1.42 (dd, J = 23.9, 6.2 Hz, 3H); ¹³C NMR (126 MHz, CDCI3) δ 165.14, 135.96, 132.56, 132.08, 129.92, 128.17, 122.48, 87.77 (d, J = 165 Hz) 61.59, 36.01, 21.14; ¹⁹F NMR (282 MHz, CDCI3) δ -176.31; MS (EI) m/z cal'd CiiHi₂BrF0₂ [M]⁺ 274.0, found 274.0;

-93- [00207] Compound 44

. Synthesized according published procedure ^XH NMR (501 MHz, CDC1₃) δ 7.97 (d, J = 8.3 Hz, 2H) 7.41 (d, J = 8.5 Hz, 2H), 4.87 (d, J = 48.6 Hz, 1H), 4.46 (m, 2H), 2.23 - 1.85 (m, 2H), 1.41 (dd, J = 23.9, 6.0 Hz, 3H); ¹³C NMR (126 MHz, CDCI3) δ 165.85, 139.70, 131.18, 128.99, 128.82, 88.05 (d, J= 166 Hz), 61.63, 36.25, 21.37; ¹⁹F NMR (282 MHz, CDCI3) δ -175.63; MS (EI) m/z cal'd C11H12CIFO2 [M]⁺ 230.1, found 230.1;

[00208] Compound 45 ^F . Synthesized according published procedure Ή NMR (501 MHz, CD3CN) δ 8.12 - 7.93 (m, 2H), 7.69 - 7.57 (m, 1H), 7.57 - 7.44 (m, 2H), 5.39 (m, 1H), 5.22 (dddt, J= 54.9, 6.2, 3.2, 1.7 Hz, 1H), 2.32 - 1.83 (m, 6H); ¹³C NMR (126 MHz, CD₃CN) δ 167.07, 134.05, 131.67, 130.25, 129.58, 96.29 (d, J = 172 Hz ), 76.79, 40.76, 32.76, 31.42; ¹⁹F NMR (282 MHz, CD₃CN) δ -169.83; MS (EI) m/z cal'd C12H13FO2 [M]⁺ 208.1, found 208.1;

[00209] Compound 46

. Synthesized according published procedure Ή NMR (501 MHz, CDCI3) δ 5.35 (br, 1H), 4.39 (dd, J= 20.4, 9.6 Hz, 1H), 3.78 (s, 3H), 1.45 (s, 9H), 1.50 - 1.37 (dd, J = 21.3, 10.3 Hz 6H); ¹³C NMR (126 MHz, CDCI3) 5170.19, 155.40, 95.26, 80.30, 60.21, 52.37, 28.27, 24.60 (d, J = 23.8 Hz), 24.34 (d, J = 24.1 Hz); ¹⁹F NMR (282 MHz, CD₃CN) δ -148.90; HRMS (ESI) m/z cal'd C11H2 +H]⁺ 250.2904, found 250.2917;

[00210] Compound 47

. Ή NMR (501 MHz, CDCI3) δ 7.83

(br, 1H), 5.21 (dt, J = 53.0, 4.2 Hz, 1H), 2.74 (m, 2H), 2.57 (m, 2H), 2.24 - 1.63 (m, 6H); ¹³C NMR (126 MHz, CDCI3) δ 171. 44, 171.34, 95.86 (d, J = 173 Hz),

-94- 45.38, 45.21, 44.46, 39.95, 35.45, 32.65; ¹⁹F NMR (282 MHz, CDC1₃) δ -167.79; HRMS (ESI) m/z cal'd C9H13FNO2 [M+H]⁺ 186.0930, found 186.0936;

[00211]

. Ή NMR (501 MHz, CDC1₃) δ 8.45 - 8.31 (m, 2H), 8.11 - 7.99 (m, 2H), 4.91 - 4.81 (br, 1H), 4.73 (dm, J= 47.6 Hz, 1H), 3.32 - 3.03 (m, 2H), 1.91 - 1.71 (m, 2H), 1.33 (dd, J= 24.3, 6.2 Hz, 3H); ¹³C NMR (126 MHz, CDCI3) δ 150.10, 145.81, 128.31, 124. 46, 89.69 (d, J= 164 Hz), 40.28, 36.48, 20.93; ¹⁹F NMR (282 MHz, CDCI3) -174.99; HRMS (ESI) m/z cal'd C₁0H₁₄FN₂O₄S [M+H]⁺ found 277.0654;

[00212] Compound 49

^IJJ NMR (501 MHz, CDCI3) δ 8.14 -

7.90 (m, 2H), 7.68 - 7.52 (m, 1H), 7.48 (m, 2H), 5.04 (dd, J = 55.2, 4.9 Hz, 1H), 4.61 (d, J= 1.7 Hz, 1H), 2.46 (dddd, J= 22.7, 14.6, 6.2, 2.4 Hz, 1H), 2.09 (dt, J = 8.1, 1.5 Hz, 1H), 1.77 - 1.31 (m, 3H), 1.26 (s, 3H), 1.17 (s, 3H), 0.82 (s, 3H); ¹³C NMR (126 MHz, CDCI3) δ 166.99, 133.15, 130.02, 129.49, 128.48, 94.18 (d, J = 177 Hz), 85.05, 53.59, 47.66, 39.06, 37.56, 37.08, 29.45, 19.39, 18.47; ¹⁹F NMR (282 MHz, CDCI3) -167.61; MS (EI) m/z cal'd C17H21FO2 [M]⁺ 276.1, found 276.1;

[00213] Compound 50

. Ή NMR (501 MHz, CD3CN) δ 4.76

(ddq, J= 54.8, 6.3, 1.3 Hz, 1H), 2.72 (d, J= 8.4 Hz, 1H), 2.61 (d, J= 4.6 Hz, 1H), 2.53 (s, 2H), 1.89 - 1.53 (m, 4H), 1.36 - 1.23 (m, 1H); Ή NMR (501 MHz, CDCI3) δ 178.04, 177.55, 93.36 (d, J= 186 Hz), 49.22, 45.20, 44.43, 38.61, 38.15, 29.91; ¹⁹F NMR (282 MHz, CD₃CN) -165.96; HRMS (ESI) m/z cal'd C9H11FNO2 [M+H]⁺ 184.0774, found 184.0779;

-95- [00214] Compound 51

. Ή NMR (501 MHz, CDC1₃) δ 8.02 -

7.96 (m, 2H), 7.61 - 7.54 (m, 1H), 7.48 (t, J = 7.6 Hz, 2H), 5.29 (d, J = 52.6 Hz, 1H), 4.04 (qd, J= 8.6, 5.6 Hz, 1H), 2.31 - 2.14 (m, 3H), 2.12 - 1.98 (m, 1H), 1.99 - 1.78 (m, 2H); ¹³C NMR (126 MHz, CDCI3) δ 201.52, 136.36, 133.14, 128.68, 128.53, 96.92 (d, J = 171 Hz), 44.02, 36.76, 32.93, 27.79; ¹⁹F NMR (282 MHz, CDCI3) -170.59; MS (EI) m/z FO [M]⁺ 192.1, found 192.1;

[00215] Compound 52

. ⁱR NMR (501 MHz, CDCI3) δ 7.61 -

7.50 (m, 2H), 7.44 - 7.34 (m, 2H), 7.32 - 7.24 (m, 1H), 5.11 (dp, =47.8, 3.3 Hz, 1H), 3.08 (br, 1H), 2.38 - 1.87 (m, 6H), 1.81 - 1.49 (m, 2H) Axial fluoride configuration is evidenced by the splitting of F-C-H (doublet ofpentet); ¹³C NMR (126 MHz, CDCI3) δ 147.59, 128.26, 126.87, 124.61, 91.54 (d, J= 164 Hz), 72.82, 42.47, 38.15, 29.92, 16.34; ¹⁹F NMR (282 MHz, CDCI3) -178.64; HRMS (ESI) m/z cal'd C12H16FO [M+H]⁺ 195.1185, found 195.1199;

[00216] Compound 53

. ⁱH NMR (501

MHz, CDCI3) δ 7.82 (dd, J= 5.5, 3.0 Hz, 2H), 7.70 (dd, J= 5.5, 3.1 Hz, 2H), 5.15 (dtt, J = 53.3, 4.8, 1.6 Hz, 1H), 3.79 (t, J = 7.0 Hz, 2H), 3.68 (t, J = 6.9 Hz, 2H), 2.82 - 2.48 (m, 4H), 2.20 - 1.45 (m, 10H); ¹³C NMR (126 MHz, CDCI3) δ 171.63, 171.59, 168.36, 133.91, 132.10, 123.21, 95.89 (d, J = 173 Hz), 45.44, 45.24, 45.07, 39.00, 38.74, 37.57, 35.23, 32.61, 26.07, 25.32; ¹⁹F NMR (282 MHz, CDCI3) -167.88; HRMS (ESI) m/z cal'd C21H24FN2O4 [M+H]⁺ 387.1720, found 387.1722;

-96- [00217] Compound

Ή NMR (501

MHz, CDCLs) δ 8.30 (d, J= 4.8 Hz, 2H), 6.47 (t, J= 4.7 Hz, 1H), 4.71 (d, J= 53.7 Hz, 1H), 3.82 (t, J = 5.1 Hz, 4H), 3.51 (t, J = 7.0 Hz, 2H), 2.92 (d, J = 8.0 Hz, 1H), 2.78 (s, 1H), 2.49 (m, 6H), 2.38 (t, J= 7.2 Hz, 2H), 1.92 - 1.35 (m, 6H), 1.25 (t, J = 7.2 Hz, 1H ) , 1.11 (d, J= 11.7 Hz, 1H); ^C NMR (126 MHz, CDC1₃) δ 177.77, 177.32, 161.64, 157.71, 109.81, 93.53 (d, J = 186 Hz), 58.05, 53.11, 47.78, 45.27, 43.65, 42.95, 38.85, 38.66, 38.19, 29.72, 25.83, 24.22; ¹⁹F NMR (282 MHz, CDCI3) δ -165.14; HRMS (ESI) m/z cal'd C21H29FN5O2 [M+H]⁺ 402.2305, found 402.2312;

[00218] Compound

. Ή NMR (500 MHz,

Chloroform-d) δ 8.14 (d, J= 8.4 Hz, OH), 8.01 (dd, J= 7.7, 1.7 Hz, OH), 2.80 (d, J = 23.1 Hz, OH), 1.55 (d, J = 22.0 Hz, 1H); ¹³C NMR (126 MHz, Chloroform- d) δ 168.18 , 141.95 , 127.13 , 125.90 - 124.58 (m), 122.14 , 120.64 , 118.27, 95.15 (d, J = 165.4 Hz), 49.72, 26.81; ¹⁹F NMR (376 MHz, Chloroform- d) δ -60.52 , - 135.37 (dqd, J = 44.3, 22.3, 8.2 Hz) ; HRMS (ESI) m/z cal'd C12H13F4N2O3 [M+H]⁺ 309.0862, found 309.0869;

[00219] Compound

. Ή NMR (501 MHz, CDCI3) δ

7.93 (td, J = 7.5, 1.8 Hz, 1H), 7.52 (dddd, J= 8.4, 7.4, 4.8, 1.9 Hz, 1H), 7.16 (m, 2H), 4.89 (dm, J = 49.6 Hz, 1H), 4.46 (m, 2H), 2.20 - 1.89 (m, 2H), 1.41 (dd, J = 23.9, 6.2 Hz, 2H); ¹³C NMR (126 MHz, CDCI3) δ 163.67 (d, J= 174 Hz), 160.92, 134.55, 132.13, 123.99, 118.67, 117.01, 87.80 (d, J = 165 Hz), 61.45, 35.97, 21.11; ¹⁹ F NMR (282 MHz, CDCI3) δ -109.32, -175.89; MS (EI) m/z cal'd C11H12F2O2 [M]⁺ 214.1, found 214.1;

-97- [00220] Compound

. Ή NMR (500 MHz, Chloroform-d) δ

6.61 (br, 1H), 5.52 (dm, J = 53.1 Hz, 1H), 4.54 (m, 1H), 2.29-1.71 (m, 6H); ¹³C NMR (126 MHz, CDC1₃) δ 156.22, 115.77 (q, J = 287.8 Hz), 96.61 (d, J = 169.1 Hz), 49.91, 40.22, 32.08, 31.03; ¹⁹ F NMR (282 MHz, CDCI3) δ -76.01, -168.03; MS(EI) m/z cal'd C7H9F4NO [M]⁺ 199.1, found 199.1;

[00221] Compound

δ 6.24

(br, 1H), 5.21 (dm, J = 53.7 Hz, 1H), 4.49, (m, 1H), 2.58 - 1.50 (m, 6H); ¹³C NMR (126 MHz, CDCI₃) δ 156.86, (q, J = 283.9 Hz), 94.45 (d, J = 173.3 Hz); 50.58, 40.35, 31.68, 30.14; ¹⁹ F NMR (282 MHz, CDC1₃) δ -76.01, -170.11; MS(EI) m/z cal'd C₇H₉F₄NO [M]⁺ 199.1, found 199.1.

[00222] New compositions of matter including the compounds set forth above, which are fluorinated derivatives of known drug molecules, were prepared and utility was demonstrated for pharmaceutical applications. Due to the nature of fluorine substitution for hydrogen in a bio-active molecule, these compounds will likely also be active, perhaps even more so than the parent compounds.

[00223] Example 13 -manganese salen mediated ¹⁸F-difluoroalkylation [00224] A large number of pharmaceuticals and bioactive molecules are difluoromethyl and difluoroalkyl- containing compounds. Therefore, these compounds are important targets for ¹⁸F labeling. However, incorporation of ¹⁸F into these difluoromethyl and difluoroalkyl-containing compounds is extremely challenging using traditional methods, and only limited progress has been achieved. No general method has been previously reported for labeling these

-98- functional groups with no-carrier-added [¹⁸F]fluoride. The method developeded for ¹⁸F labeling of difluoromethyl and difluoroalkyl functionalities ([¹⁸F]CF2R) represents the first general method for labeling these types of groups. The labeling protocol may be used the same as reported herein for manganese- catalyzed ¹⁸F labeling reaction, but using monofluoro compounds as starting substrates. The scope of fluorinated substrates and bioactive molecules is illustrated in FIG. 60.

[00225] It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but is intended to cover all modifications which are within the spirit and scope of the invention as defined by the appended claims; the above description; and/or shown in the attached drawings.

[00226] The references cited throughout this application are incorporated for all purposes apparent herein and in the references themselves as if each reference was fully set forth. For the sake of presentation, specific ones of these references are cited at particular locations herein. A citation of a reference at a particular location indicates a manner(s) in which the teachings of the reference are incorporated. However, a citation of a reference at a particular location does not limit the manner in which all of the teachings of the cited reference are incorporated for all purposes.

-99-

Claims

What is claimed is:

1. A method of direct radioactive labeling of a carbon containing compound having an sp3 C-H bond comprising: combining a carbon containing compound having an sp3 C-H bond, a fluorine radioisotope, a fluorinating catalyst, a solvent, and an oxidant, wherein the fluorinating catalyst is a manganese salen complex comprising a weakly coordinated anion as an axial ligand or a manganese porphyrin complex comprising a weakly coordinated anion as an axial ligand.

2. The method of claim 1, wherein the weakly coordinated anion is selected from the group consisting of: trifluoromethanesulfonate (OTf), toluenesulpfonate (OTs), perchlorate (CIO4), tetrafluoroborate (BF4), hexafluorophosphate (PFe), BARF ([B[3,5-(CF3)2C₆H₃] 4]), hexafluorophosphate (PF₆), hexafluoroantimonate(V) (SbFe), methanesulfonate (OMs), and 4- nitrobenzenesulfonate.

3. The method of claim 1, wherein the fluorinating catalyst is a manganese porphyrin complex that includes at least one meso-substituent in the porphyrin ring.

4. The method of claim 3, wherein the at least one meso- substituent is selected from the group consisting of: tetramesityl, tetraphenyl, pentafluorophenyl, tetradifluorophenyl, tetradichlorophenyl, tetrakis-(l,3- dimethylimidazolium-2-yl),

tetrakis (N- methylpyridinium- 2 -yl) , and tetrakis(N-methylpyridinium- 4-yl) .

5. The method of claim 1, wherein the fluorinating catalyst is a manganese porphyrin complex selected from the group consisting of: Mn(TMP)OTs,

-100- Mn(TPP)OTs, Mn(TDFPP)OTs, Mn(TDClPP)OTs, Mn(TPPFPP)OTs, Mn(TDImP)OTs, Mn(2-PyP)OTs, and Mn(4-PyP)OTs.

6. The method of claim 1, wherein the fluorinating catalyst is the manganese salen complex selected from the group consisting of: Mn(salen)OTf, Mn(salen)OTs, and Mn(salen)C10₄.

7. The method of claim 1, wherein the fluorine radioisotope is ¹⁸F.

8. The method of claim 7, wherein the ¹⁸F is an aqueous ¹⁸F fluoride.

9. The method of claim 1, the wherein the oxidant is selected from the group consisting of meta-chloroperoxybenzoic acid (mCPBA), idosylbenzene, peroxyacid, alkyl peroxide, peroxy sulfate(oxone), peroxycarbonate, peroxyborate, iodosyl mesitylene, pentafluoro-iodosylbenzene, benzene difluoroiodinane [phenyl-IF2], diacetoxyiodobenzene, 2-iodosylbenzoic acid, peroxyacetic acid, peroxyphthalic acid, and peroxytungstic acid.

10. The method of claim 1, wherein the solvent is acetone, acetonitrile or a combination thereof.

11. The method of claim 1, wherein the carbon containing compound is selected from the group consisting of: inhibitors of cyclooxygenase (COX), inhibitors of monoamine oxidase B (MAO-B), inhibitors of phosphodiesterase 10A (PDEIOA), inhibitors of angiotensin-converting enzyme (ACE), bio-messenger molecules, the neurotransmitter dopamine, fingolimod, Leucine- derivatives, Valine- derivatives, Leucine dipeptide, Boc- Valine- Luecine methyl ester, tyrosine derivative, pregabalin LYRICA^®, Boc-Amantidine, flutamide, aminocyclopentane carboxylic acid, ibuprofen, ibuprofen methyl ester, rasagiline, nabumetone, celecoxib analog, papaverine, protected enalaprilat, protected fingolimod, protected dopamine, N-Boc-cinacalcet, JNJ41510417, 5-OH-FPPAT, FEP, Acl703.

-101- BMIPP, HAR, flutemetamol, MK-9470, FACPC, CURB, MFES, FES, 2-ME, PHNO, PHNO, fallypride, DMFP, 5-OH-FPPAT, 5-OH-DPAT, NPA, NNC112, SCH, FDA, MNPA, MC113, SA4503, SA6298, BMS-747158-01, PBR28, PBR06, FMPEP, MePPEP, FBzBMS, FBFPA, FEPPA, telmisartan, tacrine, desloratadine, etodolac, cinacalcet, tanshinone IIA, indomethacin, trimethoprim, masoprocol, dubutamine, duloxetine, ondansetron, benzbromarone, simple alkanes, neopentane, toluene, cyclohexane, norcarne, simple hydrocarbons, trans- decalin, 5a-cholestane, sclarolide;, 1, 3, 5(10)-estratrien-17-one, (lR,4aS, 8aS)- octahydro-5,5,8a-trimethyl-l-(3-oxobutyl)-naphtalenone, (1R, 4S, 6S, 10S)-4, 12, 12-trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one, levomethorphan, lupine, 20- methyl-5alpha(H)-pregnane, isolongifolanone, caryophyllene acetate, N-acetyl- gabapentin methyl ester, acetyl-amantidine, phthalimido-amantadine, methyloctanoate, other saturated fatty acid esters, N-acetyl-Lyrica methyl ester, artemisinin, adapalene, finasteride, N-acetyl-methylphenidate, mecamylamine, N-acetyl-mecamylamine, N-acetyl-memantine, phthalimidi-memantine, N-acetyl- Enanapril precursor methyl ester, progesterone, artemisinin, adapalene, dopamine derivative, pregabalin, cholestane, finasteride, methylphenidate derivative, mecamylamine, gabapentin, memantine derivative, gabapentin, isoleucine derivatives, progesterone, tramadol, and (1R, 4aS, 8aS)-5, 5, 8a- trimethyl- 1 - (3- oxobutyl)octahy dr onaphthalen- 2 (1 H) -one .

12. The method of claim 1, wherein the carbon containing compound is a monofluoro containing compound having an sp3 C-H bond.

13. The method of claim 1, wherein after combining the carbon containing compound is at a concentration from 0.1 mol/L to 0.6 mol//L, the fluorine radioisotope is at a concentration from 20 μϋί/ηιΐ to 5 Ci/ml, the fluorinating catalyst is at a concentration from 0.01 mol/L to 0.03 mol/L, and the oxidant is added in a concentration from 0.05 mol/L to 0.6 mol/L.

-102-

14. The method of claim 13, wherein the volume of the solvent is 0.1 mL to 1 mL.

15. The method of claim 1, wherein the step of combining includes mixing the carbon containing compound and the fluorinated catalyst to form a first mixture, mixing the fluorine radioisotope and the solvent to form a second mixture, mixing the first mixture and the second mixture to form a third mixture, and adding the antioxidant to the third mixture.

16. The method of claim 1, wherein step of combining includes mixing the fluorine radioisotope and the solvent to form a first mixture, adding the first mixture to the fluorinating catalyst to form a second mixture, adding the second mixture to the carbon containing compound to form a third mixture, and adding the antioxidant to the third mixture.

18. The method of any one of claims 15 or 16, wherein prior to the combining the aqueous ¹⁸F-fluoride is washed in a cartridge to form a washed ¹⁸F-fluoride solution.

19. The method of claim 1 further comprising allowing the carbon containing compound, the fluorine radioisotope, the fluorinating catalyst, the solvent and the oxidant to react for 10 minutes to 30 minutes.

20. The method of claim 1, further comprising maintaining the carbon containing compound, the fluorine radioisotope, the fluorinating catalyst, the solvent and the oxidant at a temperature of 20°C to 70°C.

21. The method of claim 20, wherein the temperature is 50°C.

22. The method of claim 1 further separating a radioactively labeled product from other components obtained in the step of combining.

-103- 23. The method of claⁱm 1, wherein a radio-labeled product includes at least one compound selected from the group consisting of:

Compound

Compound

Compound

Compound

Compound

Compound

Compound 8

Compound 9

Compound 1

Compound 1

Compound 1

Compound 13

-104- Compound 1

Compound 1

Compound 1

Compound 1

Compound 1

Compound 1

Compound 20

Compound 2

Compound 2

Diastereomer

Diastereomer

Compound 24

-105- Compound 30

Compound 31

Compound 32

BocHN

Compound 33

-106- Compound 34

Compound 35 MeO

Compound 36

Compound 37

Compound 38

Compound 39

-107- Compound 41

Compound 42

Compound 43

Compound 44 CI

Compound 45

Compound 46

Compound 47

;

-108- Compound 48

Compound 49

Compound 50

Compound 51

Compound 52

Compound 53

Compound 54

-109- Compound 55

Compound 56

±)

Compound 57

Compound 58

Compound 59

Compound 60 ; and

Compound 61

wherein the F in compounds 2 - 22, the F in diastereomers 23a - 23b, the F in compounds 24 - 54, and at least one F in compounds 54 - 58 is ¹⁸F.

-110-

24. The method of claim 1, wherein a radio-labeled product is a compound selected from the group consisting of: [¹⁸F]-fluoro-inhibitors of cyclooxygenase (COX), [¹⁸F]-fluoro-inhibitors of monoamine oxidase B (MAO-B), [¹⁸F]-fluoro-inhibitors of phosphodiesterase IOA (PDEIOA), [¹⁸F]-fluoro-inhibitors of angiotensin- converting enzyme (ACE), [¹⁸F]-fluoro-bio-messenger molecules, the neurotransmitter [¹⁸F]-fluoro-dopamine, [¹⁸F]-fluoro-fingolimod, [¹⁸F]-fluoro- Leucine-derivatives, [¹⁸F]-fluoro- Valine- derivatives, [¹⁸F]-fluoro-Leucine dipeptide, [¹⁸F]-fluoro-Boc-Valine-Luecine methyl ester, [¹⁸F]-fluoro-tyrosine derivative, [¹⁸F]-fluoro-pregabalin LYRICA^®, [¹⁸F]-fluoro-Boc-Amantidine, [¹⁸F]- fluoro-flutamide, [¹⁸F]-fluoro-aminocyclopentane carboxylic acid, [¹⁸F]-fluoro- ibuprofen or the methyl ester thereof, [¹⁸F]-fluoro-rasagiline, [¹⁸F]-fluoro- nabumetone, [¹⁸F]-fluoro-celestolide, [¹⁸F]-fluoro-celecoxib analog, [¹⁸F]-fluoro- papaverine, [¹⁸F]-fluoro-protected enalaprilat, [¹⁸F]-fluoro-protected fingolimod, [¹⁸F]-fluoro-protected dopamine, [¹⁸F]-fluoro-N-Boc-cinacalcet, [¹⁸F]-fluoro- JNJ41510417, [¹⁸F]-fluoro-5-OH-FPPAT, [¹⁸F]-fluoro-FEP, [¹⁸F]-fluoro-Acl703, [¹⁸F]-fluoro-BMIPP, [¹⁸F]-fluoro-HAR, [¹⁸F]-fluoro-flutemetamol, [¹⁸F]-fluoro-MK- 9470, [¹⁸F]-fluoro-FACPC, [¹⁸F]-fluoro-CURB, [¹⁸F]-fluoro-MFES, [¹⁸F]-fluoro- FES, [¹⁸F]-fluoro-2-ME, [¹⁸F]-fluoro-PHNO, [¹⁸F]-fluoro-PHNO, [¹⁸F]-fluoro- fallypride, [¹⁸F]-fluoro-DMFP, [¹⁸F]-fluoro-5-OH-FPPAT, [¹⁸F]-fluoro-5-OH-DPAT, [¹⁸F]-fluoro-NPA, [¹⁸F]-fluoro-NNCll2, [¹⁸F]-fluoro-SCH, [¹⁸F]-fluoro-FDA, [¹⁸F]- fluoro-MNPA, [¹⁸F]-fluoro-MCll3, [¹⁸F]-fluoro-SA4503, [¹⁸F]-fluoro-SA6298, [¹⁸F]- fluoro-BMS-747158-01, [¹⁸F]-fluoro-PBR28, [¹⁸F]-fluoro-PBR06, [¹⁸F]-fluoro- FMPEP, [¹⁸F]-fluoro-MePPEP, [¹⁸F]-fluoro-FBzBMS, [¹⁸F]-fluoro-FBFPA, [¹⁸F]- fluoro-FEPPA, [¹⁸F]-fluoro-telmisartan, [¹⁸F]-fluoro-tacrine, [¹⁸F]-fluoro- desloratadine, [¹⁸F]-fluoro-etodolac, [¹⁸F]-fluoro-cinacalcet, [¹⁸F]-fluoro- tanshinone IIA, [¹⁸F]-fluoro-indomethacin, [¹⁸F]-fluoro-trimethoprim, [¹⁸F]-fluoro- masoprocol, [¹⁸F]-fluoro-dubutamine, [¹⁸F]-fluoro-duloxetine, [¹⁸F]-fluoro- ondansetron, [¹⁸F]-fluoro-benzbromarone, simple [¹⁸F]-fluoro-alkanes, [¹⁸F]- fluoro-neopentane, [¹⁸F]-fluoro-toluene, [¹⁸F]-fluoro-cyclohexane, [¹⁸F]-fluoro- norcarne, simple [¹⁸F]-fluoro-hydrocarbons, [¹⁸F]-fluoro-trans-decalin, [¹⁸F]-fluoro- 5a-cholestane, [¹⁸F]-fluoro-sclarolide, [¹⁸F]-fluoro-l, 3, 5(10)-estratrien-17-one, [¹⁸F]-fluoro-(lR,4aS, 8aS)-octahydro-5,5,8a-trimethyl-l-(3-oxobutyl)- naphtalenone, [¹⁸F]-fluoro-(lR, 4S, 6S, 10S)-4, 12, 12-trimethyl- tricyclo[8.2.0.04,6]dodecan-9-one, [¹⁸F]-fluoro-levomethorphan, [¹⁸F]-fluoro- lupine, [¹⁸F]-fluoro-20-methyl-5alpha(H)-pregnane, [¹⁸F]-fluoro-isolongifolanone, [¹⁸F]-fluoro-caryophyllene acetate, [¹⁸F]-fluoro-N-acetyl-gabapentin methyl ester, [¹⁸F]-fluoro-acetyl-amantidine, [¹⁸F]-fluoro-phthalimido-amantadine, [¹⁸F]-fluoro- methyloctanoate, other saturated [¹⁸F]-fluoro-fatty acid esters, [¹⁸F]-fluoro-N- acetyl-Lyrica methyl ester, [¹⁸F]-fluoro-artemisinin, [¹⁸F]-fluoro-adapalene, [¹⁸F]- fluoro-finasteride, [¹⁸F]-fluoro-N-acetyl-methylphenidate, [¹⁸F]-fluoro- mecamylamine, [¹⁸F] -fluoro-N-acetyl-mecamylamine, [¹⁸F] -fluoro-N-acetyl- memantine, [¹⁸F]-fluoro-phthalimidi-memantine, [¹⁸F]-fluoro-N-acetyl-Enanapril precursor methyl ester, [¹⁸F]-fluoro-progesterone, [¹⁸F]-fluoro-artemisinin, [¹⁸F]- fluoro-adapalene, [¹⁸F]-fluoro-dopamine derivative, [¹⁸F]-fluoro-pregabalin, [¹⁸F]- fluoro-cholestane, [¹⁸F]-fluoro-finasteride, [¹⁸F]-fluoro-methylphenidate derivative, [¹⁸F]-fluoro-mecamylamine, [¹⁸F]-fluoro-gabapentin, [¹⁸F]-fluoro- memantine derivative, [¹⁸F]-fluoro-isoleucine derivatives, [¹⁸F]-fluoro- progesterone, [¹⁸F]-fluoro-tramadol and [¹⁸F]-fluoro-(lR, 4aS, 8aS)-5, 5, 8a- trimethyl- 1 - (3- oxobutyl)octahy dr onaphthalen- 2 (1 H) -one .

25. The method of claim 1 further comprising obtaining an aqueous [¹⁸F] fluoride solution from a cyclotron, loading the aqueous [¹⁸F] fluoride solution onto an ion exchange cartridge, and releasing the [¹⁸F]fluoride from the ion exchange cartridge with a solution of the fluorinating catalyst.

26. The method of claim 25, further comprising rinsing the ion exchange cartridge prior to releasing.

27. The method of claim 26, wherein the rinsing is accomplished with the anyhydrous acetonitrile.

-112-

28. The method of claim 25, wherein the ion exchange cartridge is an anion exchange cartridge.

29. A method of visualization comprising: radioactively labeling a carbon containing compound having an sp3 C-H bond by the method of claim 1 , where the fluorine radioisotope includes ¹⁸F and a product produced by the method is an ¹⁸F imaging agent; administering the imaging agent to a patient; and performing positron emission tomography on the patient.

30. A composition comprising a product produced by the method of claim 1.

31. A composition comprising at least one ¹⁸F fluorinated compound selected from the group consisting of: [¹⁸F]-fluoro-inhibitors of cyclooxygenase (COX), [¹⁸F]-fluoro-inhibitors of monoamine oxidase B (MAO-B), [¹⁸F]-fluoro- inhibitors of phosphodiesterase 10A (PDEIOA), [¹⁸F]-fluoro-inhibitors of angiotensin- converting enzyme (ACE), [¹⁸F]-fluoro-bio-messenger molecules, the neurotransmitter [¹⁸F]-fluoro-dopamine, [¹⁸F]-fluoro-fingolimod, [¹⁸F]-fluoro- Leucine-derivatives, [¹⁸F]-fluoro- Valine- derivatives, [¹⁸F]-fluoro-Leucine dipeptide, [¹⁸F]-fluoro-Boc-Valine-Luecine methyl ester, [¹⁸F]-fluoro-tyrosine derivative, [¹⁸F]-fluoro-pregabalin LYRICA^®, [¹⁸F]-fluoro-Boc-Amantidine, [¹⁸F]- fluoro-flutamide, [¹⁸F]-fluoro-aminocyclopentane car boxy lie acid, [¹⁸F]-fluoro- ibuprofen or the methyl ester thereof, [¹⁸F]-fluoro-rasagiline, [¹⁸F]-fluoro- nabumetone, [¹⁸F]-fluoro-celestolide, [¹⁸F]-fluoro-celecoxib analog, [¹⁸F]-fluoro- papaverine, [¹⁸F]-fluoro-protected enalaprilat, [¹⁸F]-fluoro-protected fingolimod, [¹⁸F]-fluoro-protected dopamine, [¹⁸F]-fluoro-N-Boc-cinacalcet, [¹⁸F]-fluoro- JNJ41510417, [¹⁸F]-fluoro-5-OH-FPPAT, [¹⁸F]-fluoro-FEP, [¹⁸F]-fluoro-Acl703, [¹⁸F]-fluoro-BMIPP, [¹⁸F]-fluoro-HAR, [¹⁸F]-fluoro-flutemetamol, [¹⁸F]-fluoro-MK- 9470, [¹⁸F]-fluoro-FACPC, [¹⁸F]-fluoro-CURB, [¹⁸F]-fluoro-MFES, [¹⁸F]-fluoro- FES, [¹⁸F]-fluoro-2-ME, [¹⁸F]-fluoro-PHNO, [¹⁸F]-fluoro-PHNO, [¹⁸F]-fluoro- fallypride, [¹⁸F]-fluoro-DMFP, [¹⁸F]-fluoro-5-OH-FPPAT, [¹⁸F]-fluoro-5-OH-DPAT,

-113- [¹⁸F]-fluoro-NPA, [¹⁸F]-fluoro-NNCll2, [¹⁸F]-fluoro-SCH, [¹⁸F]-fluoro-FDA, [¹⁸F]- f uoro-MNPA, [¹⁸F]-fluoro-MCll3, [¹⁸F]-fluoro-SA4503, [¹⁸F]-fluoro-SA6298, [¹⁸F]- fluoro-BMS-747158-01, [¹⁸F]-fluoro-PBR28, [¹⁸F]-fluoro-PBR06, [¹⁸F]-fluoro- FMPEP, [¹⁸F]-fluoro-MePPEP, [¹⁸F]-fluoro-FBzBMS, [¹⁸F]-fluoro-FBFPA, [¹⁸F]- fluoro-FEPPA, [¹⁸F]-fluoro-telmisartan, [¹⁸F]-fluoro-tacrine, [¹⁸F]-fluoro- desloratadine, [¹⁸F]-fluoro-etodolac, [¹⁸F]-fluoro-cinacalcet, [¹⁸F]-fluoro- tanshinone IIA, [¹⁸F]-fluoro-indomethacin, [¹⁸F]-fluoro-trimethoprim, [¹⁸F]-fluoro- masoprocol, [¹⁸F]-fluoro-dubutamine, [¹⁸F]-fluoro-duloxetine, [¹⁸F]-fluoro- ondansetron, [¹⁸F]-fluoro-benzbromarone, simple [¹⁸F]-fluoro-alkanes, [¹⁸F]- fluoro-neopentane, [¹⁸F]-fluoro-toluene, [¹⁸F]-fluoro-cyclohexane, [¹⁸F]-fluoro- norcarne, simple [¹⁸F]-fluoro-hydrocarbons, [¹⁸F]-fluoro-trans-decalin, [¹⁸F]-fluoro- 5a-cholestane, [¹⁸F]-fluoro-sclarolide, [¹⁸F]-fluoro-l, 3, 5(10)-estratrien-17-one, [¹⁸F]-fluoro-(lR,4aS, 8aS)-octahydro-5,5,8a-trimethyl-l-(3-oxobutyl)- naphtalenone, [¹⁸F]-fluoro-(lR, 4S, 6S, 10S)-4, 12, 12-trimethyl- tricyclo[8.2.0.04,6]dodecan-9-one, [¹⁸F]-fluoro-levomethorphan, [¹⁸F]-fluoro- lupine, [¹⁸F]-fluoro-20-methyl-5alpha(H)-pregnane, [¹⁸F]-fluoro-isolongifolanone, [¹⁸F]-fluoro-caryophyllene acetate, [¹⁸F]-fluoro-N-acetyl-gabapentin methyl ester, [¹⁸F]-fluoro-acetyl-amantidine, [¹⁸F]-fluoro-phthalimido-amantadine, [¹⁸F]-fluoro- methyloctanoate, other saturated [¹⁸F]-fluoro-fatty acid esters, [¹⁸F]-fluoro-N- acetyl-Lyrica methyl ester, [¹⁸F]-fluoro-artemisinin, [¹⁸F]-fluoro-adapalene, [¹⁸F]- fluoro-finasteride, [¹⁸F]-fluoro-N-acetyl-methylphenidate, [¹⁸F]-fluoro- mecamylamine, [¹⁸F] -fluoro-N-acetyl-mecamylamine, [¹⁸F] -fluoro-N-acetyl- memantine, [¹⁸F]-fluoro-phthalimidi-memantine, [¹⁸F]-fluoro-N-acetyl-Enanapril precursor methyl ester, [¹⁸F]-fluoro-progesterone, [¹⁸F]-fluoro-artemisinin, [¹⁸F]- fluoro-adapalene, [¹⁸F]-fluoro-dopamine derivative, [¹⁸F]-fluoro-pregabalin, [¹⁸F]- fluoro-cholestane, [¹⁸F]-fluoro-finasteride, [¹⁸F]-fluoro-methylphenidate derivative, [¹⁸F]-fluoro-mecamylamine, [¹⁸F]-fluoro-gabapentin, [¹⁸F]-fluoro- memantine derivative, [¹⁸F]-fluoro-isoleucine derivatives, [¹⁸F]-fluoro- progesterone, [¹⁸F]-fluoro-tramadol and [¹⁸F]-fluoro-(lR, 4aS, 8aS)-5, 5, 8a- trimethyl- 1 - (3- oxobutyl)octahy dronaphthalen- 2 (1 H)- one

-114-

32. A composition comprising at least one ¹⁸F fluorinated compound selected from the group consisting of:

Compound 2

Compound 3

C

ompound 10

Compound 11

Compound 12

Compound 13

^■115- Compound 1

Compound 1

Compound 1

Compound 1

Compound 1

Compound 1

Compound 20

Compound 2

Compound 2

Diastereomer

Diastereomer

Compound 24

-116- Compound 30

Compound 31

Compound 32

BocHN

Compound 33

-117- Compound 34

Compound 35 MeO

Compound 36

Compound 37

Compound 38

Compound 39

-118- Compound 41

Compound 42

Compound 43

Compound 44 CI

Compound 45

Compound 46

Compound 47

;

-119- Compound 48

Compound 49

Compound 50

Compound 51

Compound 52

Compound 53

Compound 54

-120-

Compound 57

Compound 58

Compound 59

Compound 60

Compound 61

wherein the F in compounds 2 - 22, the F in diastereomers 23a - 23b, the F in compounds 24 - 54, and at least one F in compounds 54 - 58 is ¹⁸F.

33. A composition comprising carbon containing an ¹⁸F fluorinated compound

-121- that is a difluoro containing compound produced by replacing two hydrogenson a single carbom and involved in an sp3 C-H bond with ¹⁸F.

34. A method of visualization comprising: administering an imaging agent to a patient; and performing positron emission tomography on the patient, wherein the imaging agent is a compound from one of claims 31, 32, or 33.

35. A composition comprising at least two or more of a carbon containing compound, a fluorine radioisotope, a fluorinating catalyst and an oxidant.

36. A composition comprising a fluorinating catalyst, wherein the fluorinating catalyst is a manganese complex comprising a weakly coordinated anion as an axial ligand, and wherein the manganese complex is a manganese porphyrin complex or a manganese salen complex.

37. A kit comprising one or more container, wherein each container includes a composition comprising at least one reactant for a radioactive labeling selected from the group consisting of a carbon containing compound, a fluorine radioisotope, a fluorinating catalyst, and an oxidant, wherein each composition includes at least one fewer substance than required to make a fluorination reaction proceed.

38. The kit of claim 37, further comprising a container having a solvent.

39. The kit of claim 37, wherein at least one of the containers includes a solvent.

40. The kit of any one of claims 37 - 39, wherein the one or more containers in combination include all the substances required to make the fluorination reaction proceed.

-122-

41. The kit of any one of claims 37 - 40, further comprising instructions for mixing the reactants from the at least one container.

-123-