N-[18F]fluoro-N-alkylsulfonamides: novel reagents for mild and regioselective radiofluorination.

N-[18F]fluoro-N-alkylsulfonamides were synthesized by the fluorination of secondary sulfonamides with [18F]F2. Radiochemical yields up to 45% (out of a maximum possible yield of 50%) for these reactions have been realized. The N-[18F]fluorosulfonamides rapidly and regiospecifically fluorinate a variety of Grignard reagents and aryllithium under very mild conditions to give 18F-labeled derivatives in good yields.

3-(2'-[18F]fluoroethyl)spiperone, a potent dopamine antagonist: synthesis, structural analysis and in-vivo utilization in humans.

The synthesis of 3-(2'-[18F]fluoroethyl)spiperone (1c), a radiotracer useful for imaging the brain dopamine receptor system in vivo using positron emission tomography, is described. Precursors of 1c, the functional 3-N-alkyl derivatives of spiperone (4), were prepared by the alkylation of the amide group in spiperone (2a) by 1,2-disubstituted ethanes under phase transfer conditions. A comprehensive evaluation of the reaction of the derivatives 4a-h with no-carrier-added K18F/Kryptofix clearly indicated that the ketalized derivatives 4e-h were the choice of the precursors for 1c. The i.r., MS and NMR spectral data suggested that under phase transfer reaction conditions, the amide nitrogen was preferentially alkylated. To provide a firm basis for comparison with related analogues, an x-ray analysis was performed on a single crystal of 3-(2'-fluoroethyl)spiperone (1d). The tomographic behavior of 1c in human brain tissue was measured for more than 7 h and was consistent with the labeling of dopamine D-2 receptors.

Remote, semiautomated production of 6-[18F]fluoro-L-dopa for human studies with PET.

Regioselective radiofluorodemercuration of the 6-mercurio derivative 5 with [18F]acetylhypofluorite afforded, after acidic hydrolysis, 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine (6-FD, 1) with a radiochemical yield of 11% (decay corrected and based on the total amount of [18F]F2 recovered from the target). 6-FD was obtained with a chemical and radiochemical purity of greater than 99% and with a level of mercury in the final preparation of less than 20 ppb. Utilization of a remote, semiautomated production system, resulted in the preparation of a sterile, pyrogen-free product suitable for human injection after a synthesis time of 50 min.

Computer-controlled radiochemical synthesis: a chemistry process control unit for the automated production of radiochemicals.

A computer-controlled general purpose chemistry process control unit (CPCU) suitable for the automated production of radiochemicals has been developed. This valve-and-tubing synthesis system can be user programmed to accommodate a variety of chemical processes. In a practical demonstration of its utility, the CPCU has been configured and programmed to synthesize 2-deoxy-2-[18F]fluoro-D-glucose (2-[18F]FDG) using aqueous [18F]fluoride ion. Using this instrument, the yield of 2-[18F]FDG from [18F]fluoride ion is 54.9% (+/- 11.2%, n = 125) corrected to EOB, after a synthesis time of 50-55 min. The average total activity produced (for runs of 5-10 microA) is 28.1 mCi/microA (+/- 5.03 mCi/microA). Thus, the amount of 2-[18F]FDG produced from a 10 microA for 1 h bombardment was 154.3 mCi (+/- 27.4 mCi). The unit has been similarly configured and programmed to synthesize 2-deoxy-2-[18F]fluoro-D-mannose (48% EOB), 3-(2'-[18F]fluoroethyl)spiperone (29% EOB), and [18F]fluoroacetate (66% EOB) from aqueous [18F]-fluoride ion, and 2-[18F]FDG from gaseous acetyl hypo[18F]fluorite (20% EOB).

No-carrier-added 3-(2'-[18F]fluoroethyl)spiperone, a new dopamine receptor-binding tracer for positron emission tomography.

No-carrier-added (NCA)3-(2'-[18F]fluoroethyl)spiperone (5), a new dopamine receptor-binding radiopharmaceutical for positron emission tomography, was synthesized by two different methods. Alkylation of the amide nitrogen in spiperone by NCA [18F]fluorobromoethane in the presence of a strong base gave 5 (Method A). Experimental methods were also developed for the syntheses of functional 3-N-alkylderivatives of spiperone such as 3-(2'-bromoethyl)- or 3-(2'-methylsulfonyloxyethyl)spiperone (4a and 4b, respectively). These derivatives (4) reacted with NCA Ag18F, Cs18F or K18F/Kryptofix 222 in acetonitrile or DMSO to give 5 (Method B). Method B, using K18F/Kryptofix 222 in acetonitrile provided 5 in multimillicure amounts (30-40% isolated radiochemical yield) with a specific activity of 2-10/mumol (EOS) in less than 60 min. This one-step, one-pot synthesis is simple, and the high radiochemical yield of 5, as well as the 110 min half-life of 18F, permit multiple tomographic studies a day with one preparation. Tomographic results in monkey brain with 5 are consistent with the labeling of dopamine-D2 receptor systems.

Stereospecific approach to the synthesis of [18F]2-deoxy-2-fluoro-D-mannose.

The reaction of methyl 4,6-O-benzylidene-3-O-benzyl-2-O-trifluoromethanesulfonyl-beta-D- glucopyranoside in acetonitrile at 75 degrees C for 30 min with [18F]tetra-n-butylammonium fluoride, followed by silica gel column chromatographic purification, gave the corresponding [18F]methyl 4,6-O-benzylidene-3-O-benzyl-2-fluoro-beta-D-mannopyranoside with complete regio- and stereoselectivity (42% radiochemical yield). Hydrolysis of the radiolabeled fluoromannopyranoside intermediate with either 6 N HCl or 50% methanesulfonic acid for 30 min at 120 degrees C, followed by purification by column chromatography (ion retardation resin and neutral alumina), gave pure [18F]2-deoxy-2-fluoro-D-mannose ([18F]2-FDM) with an overall radiochemical yield (from [18F]fluoride ion) of 34%. Extension of this methodology to the no carrier added (nca) synthesis under phase transfer conditions (Kryptofix 222/K 18F/acetonitrile) gave nca [18F]2-FDM in a radiochemical yield of 75%. Purity and identity of the fluorinated products were confirmed by 1H and 19F NMR spectroscopy. The synthetic procedure described here permits for the first time the routine preparation of large amounts of [18F]2-FDM for tomographic studies.

The synthesis of 2-[F-18]fluoro-2-deoxy-D-glucose using glycals: a reexamination.

The reaction of [F-18]F2 with D-glucal in water proceeds sufficiently mildly at room temperature to present marked regiospecificity. After hydrolysis, analysis by Fourier-transform 19F-NMR showed the product to consist of a mixture of 2-fluoro-2-deoxy-D-glucose (2-FDG) and 2-fluoro-2-deoxy-D-mannose (2-FDM) in a 2:1 ratio, respectively. The presence of the mannose isomer has been revealed by extension of the 19F-NMR analyses to other literature methods for 2-FDG synthesis involving the electrophilic fluorinating agent acetyl hypofluorite. Reaction of acetyl [F-18] hypofluorite, prepared by the reaction of [F-18]F2 with solid sodium acetate trihydrate, with the appropriate glycal/solvent combination, followed by hydrolysis, has led to production of [F-18]2-FDG with a radiochemical purity of 95%.

The effect of target-gas purity on the chemical form of F-18 during 18F-F2 production using the neon/fluorine target.

Irradiation of gas mixtures of F2/Ne (20Ne leads to d,alpha 18F) which contained percent levels ( > 0.1%) of N2, CO2, CO2, or CF4 resulted in the production of unacceptable levels of F-18-labeled NF3 and CF4 at the expense of 18F-F2. Analycical gas chromatographic methods have been devised to determine contaminant levels in the target gas as well as in the products arising from them. Commercial mixtures of 1T F2/Ne, pur F2, and neon have been analyzed for contaminants (N2, O2, CO, CO2, and CF4) and found to vary widely in the levels of these impurities from batch to batch. The N2 levels in the 1% F2/Ne mixtures varied from 0.039 to 0.49%, and the CO2 levels from 0o.018 to 0.13%. No detectable impurities were found in the neon (Research Purity), but F2 was found to contain approximately 11% CF4. Reproducibly high yields of 18F-F2 are obtained if the levels of N2, CO2, and CF4 in the final target gas mixture are < 0.01% and carrier F2 is approximately 0.1%. Hydrocarbons and CO were not detected in our gas mixtures, but would also be expected to decrease yields of 18F-F2.