Process for deoxyfluorination of phenols

Abstract

The present invention refers to a process for transition-metal-assisted .sup.18F-deoxyfluorination of phenols. The transformation benefits from readily available phenols as starting materials, tolerance of moisture and ambient atmosphere, large substrate scope, and translatability to generate doses appropriate for positron emission tomography (PET) imaging.

Claims

1. A method of replacing a hydroxyl group on an aryl or heteroaryl compound bearing the hydroxyl group with a fluorine atom, the method comprising contacting a compound of Formula (I): ##STR00027## with a Cp-Ru-(aryl or heteroaryl)-complex in the presence of a fluorine source under conditions sufficient to fluorinate the aryl or heteroaryl compound bearing the hydroxyl group compound, thereby providing a fluorinated (aryl or heteroaryl) compound, wherein, in Formula (I): R.sup.1 and R.sup.2 are independently selected from the group consisting of C1-30 aliphatic, aromatic, heteroaliphatic or heteroaromatic hydrocarbons, each of which is optionally substituted with at least one substituent selected from C1-20 straight chain, branched or cyclic alkyl, alkenyl, alkynyl, aryl, heteroaryl, each being optionally further substituted by one or more heteroatoms, or heteroatoms, R.sup.3 and R.sup.4 are independently selected from the group consisting of C1-30 aliphatic, aromatic, heteroaliphatic or heteroaromatic hydrocarbons, each of which is optionally substituted with at least one substituent selected from C1-20 straight chain, branched or cyclic alkyl, alkenyl, alkynyl, aryl, heteroaryl, each being optionally further substituted by one or more heteroatoms, or heteroatoms, or R.sup.3 and R.sup.4 together with N—C═N to which they are bonded form a C4-20 ring which may be saturated or unsaturated aliphatic or aromatic, which C4-20 ring is optionally substituted with at least one substituent selected from C1-20 straight chain, branched or cyclic alkyl, alkenyl, alkenyl, aryl, heteroaryl, the C4-20 ring being optionally further substituted by one or more heteroatoms, or heteroatoms, and the C4-20 ring optionally fused to a C5-20 hydrocarbon ring which may be unsaturated or saturated aliphatic or aromatic including heteroatoms, which C5-20 hydrocarbon ring is optionally substituted by at least one substituent selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, nitro, cyano, halo, C1-6 haloalkyl, C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, and acyl, each substituent for the C5-20 hydrocarbon ring being optionally further substituted by one or more heteroatoms; X being an anion; and L being a leaving group, wherein the Cp-Ru-(aryl or heteroaryl)-complex is a Ru complex with a C5 to C30 aromatic or heteroaromatic mono- to polycyclic ring system having at least one aromatic or heteroaromatic ring with one hydroxyl group on said ring, said ring system optionally being further substituted with straight chain, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 20 carbon atoms, or heteroatoms being selected from halogen, N, O or S, each of said alkyl, alkenyl, alkynyl, or heteroatoms being optionally further substituted or each of said alkyl, alkenyl, alkynyl, or heteroatoms being optionally part of an aliphatic or aromatic ring system, and at least one further ligand optionally being further substituted by one or more heteroatoms or by C1-6 alkyl, optionally being further substituted with halogen.

2. The method according to claim 1, wherein the compound of Formula (I) has the Formula (II): ##STR00028## and the method comprises contacting a compound of Formula (II) with the Cp-Ru-(aryl or heteroaryl)-complex and a fluorine source under conditions sufficient to fluorinate the aryl or heteroaryl compound bearing the hydroxyl group, thereby providing a fluorinated aryl compound, wherein, in Formula (II): R.sup.1 and R.sup.2 are independently selected from the group consisting of C1-6 alkyl, C6-10 aryl, C6-10 aralkyl, 5-10 membered heteroaryl, 5-10 membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 membered carbocyclylalkyl, each being optionally further substituted by one or more heteroatoms; R.sup.5 and R.sup.6 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, nitro, cyano, halo, C1-6 haloalkyl, C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, each being optionally further substituted by one or more heteroatoms; or R.sup.5 and R.sup.6 may form together a C5-20 hydrocarbon ring which may be unsaturated or saturated aliphatic or aromatic including heteroatoms, optionally being substituted by C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, nitro, cyano, halo, C1-6 haloalkyl, C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, each being optionally further substituted by one or more heteroatoms; X being an anion; and L is a leaving group, wherein the Cp-Ru-(aryl or heteroaryl)-complex is a Ru complex comprising an aryl or heteroaryl compound bearing a hydroxyl group as a ligand and at least one further ligand optionally being substituted by C1-6 alkyl, haloalkyl or halogen.

3. The method according to claim 2, wherein in Formula (II): R.sup.1 and R.sup.2 are independently selected from the group consisting of C6-10 aryl, C6-10 aralkyl, 5-10 membered heteroaryl, 5-10 membered heteroaralkyl, each of which is optionally substituted at least one substituent selected from the group consisting of halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, optionally substituted with at least one heterosubstituent; R.sup.5 and R.sup.6 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, optionally substituted with at least one heterosubstituent, L is a leaving group which is not detrimentally interacting in the method; and X represents an anion.

4. The method according to claim 2, wherein the compound of Formula (II) is represented by the following formula (III): ##STR00029## wherein each R.sup.7 is independently selected from halogen, optionally substituted C1-8 alkyl, in particular iso-propyl, C1-8 haloalkyl, C1-8 alkoxy, optionally substituted C6-12 aryl, and optionally substituted 6-12 membered heteroaryl, and wherein “substituted” refers to substituted with a substituent selected from the group consisting of alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy, halogen, hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkylamino, dialkylamino, sulfate, phosphate, methylenedioxy —O—CH.sub.2—O— wherein oxygens are attached to vicinal atoms, ethylenedioxy, oxo, thioxo (e.g., C═S), imino (alkyl, aryl, aralkyl), S(O).sub.n-alkyl (where n is 0-2), S(O).sub.n-aryl (where n is 0-2), S(O).sub.n-heteroaryl (where n is 0-2), S(O).sub.n-heterocyclyl (where n is 0-2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof), ester (alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl), amide (mono-, di-, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof), sulfonamide (mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof), and wherein L and X are selected from halide ions or carboxylate ions.

5. The method according to claim 1, wherein L and X are selected from halide ions or carboxylate ions.

6. The method according to claim 1 wherein the fluorine source is a fluoride salt.

7. The method according to claim 1, wherein the fluorine source is a sodium, potassium, or cesium fluoride salt.

8. The method according to claim 1, wherein the fluoride source comprises .sup.18F.

9. The method according to claim 1, wherein the fluoride source comprises .sup.19F.

10. The method according to claim 1, wherein the Ru phenol complex is a Ru complex with an aryl compound bearing one hydroxyl as a ligand and one cyclopentadienyl ligand, optionally being substituted.

11. A complex of the general formula (IV): ##STR00030## wherein in said formula (IV): ##STR00031## represents a C5 to C30 aromatic or heteroaromatic mono- to polycyclic ring system having at least one aromatic or heteroaromatic ring and one oxygen O.sup.B bound on said aromatic or heteroaromatic ring, said ring system optionally being further substituted with at least one substituent R.sub.p selected from straight chain, branched or cyclic alkyl, alkenyl, alkynyl, aryl, heteroaliphatic or heteroaryl each having 1 to 20 carbon atoms, each being optionally further substituted by one or more heteroatoms, or a heteroatom, R.sup.1 and R.sup.2 are independently selected from the group consisting of C1 to C30 aliphatic, aromatic, heteroaliphatic or heteroaromatic hydrocarbons, each of which is optionally substituted with at least one substituent selected from C1-20 straight chain, branched or cyclic alkyl, alkenyl, alkynyl, aryl, heteroaryl or heteroatoms, each being optionally further substituted by one or more heteroatoms, R.sup.3 and R.sup.4 are independently selected from the group consisting of C1-30 aliphatic, aromatic, heteroaliphatic or heteroaromatic hydrocarbons, each of which is optionally substituted with at least one substituent selected from C1-20 straight chain, branched or cyclic alkyl, alkenyl, alkynyl, aryl, heteroaryl or heteroatoms, each being optionally further substituted by one or more heteroatoms, or R.sup.3 and R.sup.4 with N—C═N to which they are bonded form a C4-20 ring which may be saturated or unsaturated aliphatic or aromatic, which C4-20 ring is optionally substituted with at least one substituent selected from C1-20 straight chain, branched or cyclic alkyl, alkenyl, alkynyl, aryl, heteroaryl or heteroatoms, the C4-20 ring being optionally further substituted by one or more heteroatoms, and the C4-20 ring optionally fused to a C5-20 hydrocarbon ring which may be unsaturated or saturated aliphatic or aromatic including heteroatoms, which C5-20 hydrocarbon ring is optionally substituted by at least one substituent selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, nitro, cyano, halo, C1-6 haloalkyl, C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, and acyl, each substituent for the C5-20 hydrocarbon ring being optionally further substituted by one or more heteroatoms; and X being an anion.

12. Process for converting a complex of the general formula (IV) as defined in claim 11 into a Cp-Ru-(aromatic or heteroaromatic mono- to polycyclic ring)F complex comprising treating the complex of general formula (IV) with a fluorine source.

13. Process according to claim 12, further comprising decomplexing the Cp-Ru-(aromatic or heteroaromatic mono- to polycyclic ring)F complex whereby a fluorinated aromatic or heteroaromatic mono- to polycyclic ring is obtained.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention is further illustrated by the attached Figures.

(2) FIG. 1. Synthesis of β-CFT via ruthenium-mediated deoxyfluorination. RCY.sub.HPLC=Radiochemical yield determined as fraction of product radioactivity of total counts by radio-HPLC;

(3) FIG. 2a and FIG. 2b.

(4) 2a) Concerted nucleophilic aromatic substitution (CS.sub.NAr) via B to furnish the fluorinated arene. K.sub.1: equilibrium constant. Ar=2,6-diisopropylphenyl

(5) 2b) The ruthenium fragment decreases the electron density of the phenol, which renders the tetrahedral intermediate more favorable—K.sub.2>>K.sub.1. Isotopologue [.sup.19F]6 was synthesized from 5 in 75% yield to confirm the identity of [.sup.18F]6;

(6) FIG. 3. Substrate table for ruthenium-mediated .sup.18F-deoxyfluorination of phenols. RCY.sub.TLC=Radiochemical yield determined as fraction of product radioactivity of total counts by radio-TLC; *26% activity yield;

(7) FIG. 4. Fully automated ruthenium-mediated .sup.18F-deoxyfluorination of tyrosine derivative. 111 mCi (4.11 GBq) activity yield AY (24.1%) is non-decay-corrected. As shown in FIG. 3, heating the air and moisture stable Ru complex CpRu(COD)Cl (1) with a phenol in ethanol for 30 min at 85° C. affords a solution of ruthenium phenol complex, e.g. 5, subsequent addition of chloroimidazolium chloride 2 provides a solution, which is used to elute .sup.18F-fluoride off an anion exchange cartridge. After addition of a 1:1 DMSO/acetonitrile (v/v) solution, the reaction mixture is heated for 30 min to afford aryl fluorides. No precautions to exclude moisture or air are necessary at any point in the process.

(8) As regards the experimental results, in line with the inventors' goal, electron-rich substrates like anisole (7a) and dialkylaniline derivatives (7c) show high radiochemical yields by TLC(RCY.sub.TLC). A variety of functional groups is tolerated, most importantly basic amines (7b, c, i, l) which can present a major limitation to several available radiofluorination methods. Protic functional groups (7e, j, n) are unproblematic and phenolic hydroxyl groups can be selectively deoxyfluorinated in the presence of unprotected aliphatic alcohols without affecting carbinol stereochemistry (7h, l). Additionally, several heterocyclic scaffolds, including pyrimidines (7m), indoles (7o) and quinolines (7k) are good substrates for the reaction. Ortho-substitution is tolerated (7k, o).

(9) The overall yield of the reaction is affected by the RCY and elution efficiency (EE) of [.sup.18F]fluoride off the anion exchange cartridge, and both were addressed when optimizing reaction conditions. Chloride as X-type ligand for CpRu(COD)X gave higher yields than other evaluated ligands. EE and RCY improved with higher concentration and molar excess of both 1 and 2. The minimal increases in yield obtained by more than three equivalents of 1 and 2 did not justify the expenditure of reagents and additional purification difficulties. Both EE and RCY were higher when ethanol was present in the reaction mixture. While more than 30% ethanol was detrimental to the fluorination, low solvent volumes were impractical to handle, and the inventors continued the inventors' work with 50 μL ethanol in 400 μL total reaction volume. Although several salt additives increased elution efficiency, the gain was offset by a reduction in RCY. None of the additives investigated improved the overall yield. Reaction temperatures below 125° C. and reaction times less than 30 min afforded lower yields of product.

(10) For any .sup.18F-radiolabeling methodology to be practically useful, it needs to be amenable to automation on commercial radiosynthesis modules. On an Elixys (Sofie Biosciences) radiosynthesizer, the inventors were able to perform the reaction in a fully automated fashion: From 461 mCi (17.1 GBq) of .sup.18F-fluoride obtained in aqueous solution from a cyclotron, the inventors were able to isolate 111 mCi (4.11 GBq) of purified, protected .sup.18F-fluorophenylalanine derivative 9 within 80 min (FIG. 4). Additional reformulation and filtration, as is required for human PET tracer synthesis, formally resulted in 82.3 mCi (3.05 GBq) of reformulated, purified 9 (see SI for detail). The stereochemical purity of the starting material was maintained throughout the reaction. Initially, yields of the automated syntheses were more than tenfold lower than in manual experiments. The main factors responsible for the lower yields were identified as vial size and the associated headspace, and the use of 4 mL instead of 10 mL reactors resolved the issue. It is crucial to ensure that an internal temperature of 125° C. is reached when using a vial adapter. In commercial radiosynthesis systems for which smaller vials are not commonly available, high pressure is an alternative strategy to counteract the larger headspace. For example, in a Siemens Explore FDG4 system, an increase in pressure from 30 kPa to 205 kPa during the reaction improved the RCY toward protected fluorophenylalanine fivefold (see SI for details).

(11) The PhenoFluor reagent is known to facilitate a concerted nucleophilic aromatic substitution mechanism, which enables deoxyfluorination of electron-rich phenol substrates..sup.[6] The inventors' computational results (see FIG. 1) suggest that coordination of the RuCp fragment withdraws sufficient electron density from the phenol substrate that a classic S.sub.NAr mechanism via a Meisenheimer complex (MHC) is preferred. DFT-calculated reaction barriers are 5.3 kcal.Math.mol.sup.−1 for fluoride attack (TS.sub.1) and 7.0 kcal.Math.mol.sup.−1 for leaving group loss (TS.sub.2). The inventors consider the barriers remarkably low for C—F bond formation, and, hence, the potential of η.sup.6-coordination for radiofluorination of other arene electrophiles may be a promising research endeavor. Attempts to isolate reaction intermediates in the deoxyfluorination of phenols with .sup.19F-fluoride only yielded the aryl fluoride product complexed to Ru (eg. 6), which corroborates the low deoxyfluorination barriers obtained computationally. Decomplexation of the aryl fluoride product from the Ru fragment requires elevated reaction temperatures, and, currently, is the rate-limiting step in the sequence. Because [.sup.18F]fluoroarene dissociation is rate-limiting, the inventors note that [.sup.18F]fluoroarene complexed to the RuCp fragment can be observed as byproduct if reaction times are too short.

(12) The ruthenium-mediated dexoyfluorination presents a valuable addition to the radiochemical toolbox. Very electron rich substrates are challenging to fluorinate with conventional radiofluorination reactions, but unproblematic for this approach. Basic amines and ortho-substitution are fully compatible. The substrates are readily accessible and stable phenols. The reaction is operationally simple, can be executed in air in the presence of moisture, and automation is established. The method is broadly applicable and easy to adapt in a radiopharmaceutical production environment.

(13) The invention is further illustrated by the following exemplary preparations.

(14) Experimental Part

(15) General Procedure for [.sup.18F]Deoxyfluorination of Phenols

(16) ##STR00009##

(17) A phenol (8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (12 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(18) Target water from the cyclotron containing .sup.18F-fluoride (typically 50 uL) was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (Table S1). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of phenol-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (Table S1). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The products were characterized by comparing the radio-HPLC trace of the reaction mixtures with the HPLC UV traces of the authentic reference samples, respectively.

(19) All .sup.18F-labeled molecules were characterized by comparing the retention time of the product (γ-trace) to the retention time of an authentic reference sample. Note: radioactivity chromatographs are offset by 0.15 min on account of the delay introduced by the spatial separation between the diode array detector and the radioactivity detector.

(20) TABLE-US-00001 TABLE S1 The amounts of initial radioactivity trapped, the amount eluted, and the RCYs of [.sup.18F]deoxyfluorination of phenols, estimated by TLC. Initial Eluted Elution radioactivity radioavtivity efficiency RCY Entry Product (mCi, GBq) (mCi, GBq) (%) (%) 1 4 8.0, 0.30 5.1, 0.19 64 67 2 7a 7.5, 0.28 4.9, 0.18 66 89 3 7b 5.9, 0.22 4.4, 0.16 75 85 4 7c 5.2, 0.19 3.3, 0.12 63 99 5 7d 6.2, 0.23 4.6, 0.17 73 88 6 7e 4.2, 0.16 3.0, 0.11 71 30 7 7f 4.3, 0.16 2.7, 0.10 64 82 8 7g 6.9, 0.26 4.0, 0.15 58 10 9 7h 5.9, 0.22 3.9, 0.14 66 98 10 7i 5.6, 0.21 3.1, 0.12 55 99 11 7j 7.2, 0.27 4.8, 0.18 67 99 12 7k 6.0, 0.22 4.6, 0.17 77 85 13 7l 6.5, 0.24 3.5, 0.13 54 80 14 7m 5.1, 0.20 3.5, 0.13 67 43 15 7n 7.3, 0.27 4.6, 0.17 62 99 16 7o 10.7, 0.40 6.8, 0.25 64 88 17 7p 6.0, 0.22 3.0, 0.11 49 62

(21) [.sup.18F]-β-CFT (4)

(22) ##STR00010##

(23) Phenol 3 (3.9 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(24) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (8.0 mCi, 0.30 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of 3-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (5.1 mCi, 0.19 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product [.sup.18F]-β-CFT (4) was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample. The authentic reference (β-CFT) (5 mg) was purchased from Sigma-Aldrich as β-CFT naphthalenedisulfonate monohydrate and then the naphthalenedisulfonate was removed from the sample using 5 coupled Sep-Pak Plus C18 Environmental Cartriges (WAT036800) from Waters connected in series. The sample was loaded onto the C18 cartridges, and a HPLC pump was used for elution with the following mobile phases: 0.1% formic acid in water (A), 0.1% formic acid in acetonitrile (B). Program: starting from 5% (B) to 95% (B) as a gradient over 12 min with flow rate 4.0 mL/min.

(25) [.sup.18F]1-(Fluoro)-4-methoxybenzene (7a)

(26) ##STR00011##

(27) 4-Methoxyphenol (1.1 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(28) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (7.5 mCi, 0.28 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of 4-methoxyphenol-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (4.9 mCi, 0.18 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7a was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(29) [.sup.18F]Benzylpiperazin 7b

(30) ##STR00012##

(31) Phenol S5 (1.7 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(32) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (5.9 mCi, 0.22 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of S5-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (4.4 mCi, 0.16 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7b was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(33) [.sup.18F]Piperazin 7c

(34) ##STR00013##

(35) 1-(4-(4-Hydroxyphenyl)piperazin-1-yl)ethan-1-one (1.9 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(36) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (5.2 mCi, 0.19 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of 1-(4-(4-hydroxyphenyl)piperazin-1-yl)ethan-1-one-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (3.3 mCi, 0.12 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7c was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(37) [.sup.18F]Estrone 7d

(38) ##STR00014##

(39) Estrone (2.3 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(40) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (6.2 mCi, 0.23 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of estrone-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (4.6 mCi, 0.17 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7d was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(41) [.sup.18F](4-(Fluoro)phenyl)methanamine (7e)

(42) ##STR00015##

(43) 4-(Aminomethyl)phenol (1.1 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(44) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (4.2 mCi, 0.16 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of 4-(aminomethyl)phenol-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (3.0 mCi, 0.11 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7e was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(45) Note: Lewis basic compounds, such as amines, can form unproductive ruthenium coordination compounds. These are typically visible by HPLC as broad peaks within the first minutes after the solvent front. We attribute the relatively low yield of 7e to the formation of such compounds and consequently suggest protection of primary amines, despite fundamental compatibility with the reaction.

(46) [.sup.18F]Ethyl 3-(fluoro)-9H-carbazole-9-carboxylate (7f)

(47) ##STR00016##

(48) Ethyl 3-hydroxy-9H-carbazole-9-carboxylate (2.2 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(49) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (4.3 mCi, 0.16 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of ethyl 3-hydroxy-9H-carbazole-9-carboxylate-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (2.7 mCi, 0.10 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7f was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(50) [.sup.8F]Phenothiazin 7q

(51) ##STR00017##

(52) Phenol S10 (2.6 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(53) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (6.9 mCi, 0.26 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of S10-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (4.0 mCi, 0.15 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7g was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(54) [.sup.18F]Fluorodeoxyezetimibe (7h)

(55) ##STR00018##

(56) Ezetimibe (S19) (3.5 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(57) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (5.9 mCi, 0.22 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of S19-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (3.9 mCi, 0.14 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7h was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(58) [.sup.18F](4-(3-(Fluoro)phenyl)morpholine) (7i)

(59) ##STR00019##

(60) 3-Morpholinophenol (1.5 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(61) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (5.6 mCi, 0.21 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of 3-morpholinophenol-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (3.1 mCi, 0.12 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7i was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(62) [.sup.18F]4-Fluorobenzanilide (7j)

(63) ##STR00020##

(64) N-(4-Hydroxyphenyl)benzamide (S11) (1.8 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(65) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (7.2 mCi, 0.27 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of S11-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (4.8 mCi, 0.18 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7j was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(66) [.sup.18F]4-(Fluoro)-2-phenylquinoline (7k)

(67) ##STR00021##

(68) 2-Phenylquinolin-4-ol (1.9 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(69) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (6.0 mCi, 0.22 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of 2-phenylquinolin-4-ol-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (4.6 mCi, 0.170 Bq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7k was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(70) [.sup.18F]Purin 7l

(71) ##STR00022##

(72) Purin S13 (3.9 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(73) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (6.5 mCi, 0.24 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of S13-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (3.5 mCi, 0.13 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7l was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(74) [.sup.18F]5-Bromo-2-(fluoro)pyrimidine (7m)

(75) ##STR00023##

(76) 5-Bromopyrimidin-2-ol (1.5 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(77) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (5.1 mCi, 0.19 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of 5-bromopyrimidin-2-ol-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (3.5 mCi, 0.13 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7m was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(78) Figure S45. UV-HPLC trace of 5-bromo-2-fluoropyrimidine as the reference.

(79) [.sup.18F]L-tyrosinate 7n

(80) ##STR00024##

(81) Methyl (tert-butoxycarbonyl)-L-tyrosinate (2.5 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(82) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (7.3 mCi, 0.27 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of methyl (tert-butoxycarbonyl-L-tyrosinate-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (4.6 mCi, 0.17 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7n was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(83) [.sup.18F]Ethyl 4-(fluoro)-1H-indole-1-carboxylate (7o)

(84) ##STR00025##

(85) Ethyl 4-hydroxy-1H-indole-1-carboxylate (1.7 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(86) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (10.7 mCi, 0.40 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of ethyl 4-hydroxy-1H-indole-1-carboxylate-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (6.8 mCi, 0.25 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7o was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(87) [.sup.18F]Chromane 7p

(88) ##STR00026##

(89) (+)-δ-Tocopherol (S25) (3.4 mg, 8.7 μmol, 1.0 eq.) and [CpRu(cod)Cl] (1) (8.0 mg, 26 μmol, 3.0 eq.) were added to EtOH (50 μL, c=0.80 M) in a 0.5 dram (1.8 mL) borosilicate glass vial. The vial was capped, and the reaction mixture was stirred at 85° C. (heating block temperature) for 30 min. The vial was removed from the heating block and allowed to stand for 3 min at 23° C. To the vial, imidazolium chloride 2 (14 mg, 26 μmol, 3.0 eq.) and 150 μL of MeCN were added, and the resulting solution mixture was drawn into a 1.0 mL polypropylene syringe.

(90) Target water from the cyclotron containing .sup.18F-fluoride was loaded with a syringe onto a QMA anion exchange cartridge (Chromafix 30-PS—HCO.sub.3) and the radioactivity of the trapped .sup.18F-fluoride was measured (6.0 mCi, 0.22 GBq). The cartridge was washed with MeCN (1.0 mL). The cartridge was inverted and fitted with a female×female Luer adapter. With the syringe, which contained the corresponding solution of S25-ruthenium complex and 2, the .sup.18F-fluoride was eluted into a 1 dram (3.7 mL) borosilicate vial. The cartridge was washed with DMSO (150 μL), followed by DMSO: MeCN (50 μL, 1:1 (v/v)) and the radioactivity of the eluted solution was measured (3.0 mCi, 0.11 GBq). The reaction vial, which contained 400 μL of the reaction mixture was sealed with a teflon-lined cap and was heated at 125° C. for 30 min. The vial, which contained the reaction mixture was removed from the heat and was allowed to stand for 3 min at 23° C. The reaction mixture was analyzed by radio-HPLC and radio-TLC. The product 7p was characterized by comparing the radio-HPLC trace of the reaction mixture with the HPLC UV traces of the authentic reference sample.

(91) Kits

(92) The compounds used in the methods described herein (e.g., a hydroxy aryl or heteroaryl compound, the Ru complex and a fluorinating agent) may be provided in a kit. The kit includes (a) a compound used in a method described herein (e.g., a compound of formulas (I) and (II)), the Ru complex and, optionally (b) informational material. The informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the compounds for the methods described herein.

(93) The informational material of the kits is not limited in its form. In one embodiment, the informational material can include information about production of the compound, molecular weight of the compound, concentration, date of expiration, batch or production site information, and so forth. In one embodiment, the informational material relates to methods for using the compound.

(94) The informational material of the kits is not limited in its form. In many cases, the informational material, e.g., instructions, is provided in printed matter, e.g., a printed text, drawing, and/or photograph, e.g., a label or printed sheet. However, the informational material can also be provided in other formats, such as Braille, computer readable material, video recording, or audio recording. In another embodiment, the informational material of the kit is contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about a compound described herein and/or its use in the methods described herein. Of course, the informational material can also be provided in any combination of formats.

(95) In some embodiments, the components of the kit are stored under inert conditions (e.g., under Nitrogen or another inert gas such as Argon). In some embodiments, the components of the kit are stored under anhydrous conditions e.g., with a desiccant). In some embodiments, the components are stored in a light blocking container such as an amber vial.

(96) A compound described herein can be provided in any form, e.g., liquid, dried or lyophilized form. It is preferred that a compound described herein be substantially pure and/or sterile. When a compound described herein is provided as a dried form, reconstitution generally is by the addition of a suitable solvent.

(97) The kit can include one or more containers for the composition containing a compound described herein. In some embodiments, the kit contains separate containers, dividers or compartments for the composition and informational material. For example, the composition can be contained in a bottle, vial, or ampule, and the informational material can be contained in a plastic sleeve or packet. In other embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the composition is contained in a bottle, vial or ampule that has attached thereto the informational material in the form of a label. In some embodiments, the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms (e.g., a dosage form described herein) of a compound described herein. The containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight.

(98) As illustrated above, the new fluorinating process is suitable for site-specific substitution of hydroxyl groups with non-carrier-added 18F-fluoride in a one-step transformation. The transformation combines the substrate scope of late-stage fluorination with the convenient and broadly implemented reaction setup of simple displacement chemistry.

(99) The use of readily available phenols as precursors allows rapid access to new PET probes. Development of this method of radiofluorination into a fully automated, versatile 18F-labeling protocol would considerably streamline tracer development through the synthesis of desirable PET probes.