Gerald T. Bida

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

Abstract Regioselective radiofluorodemercuration of the 6-mercurio derivative 5 with [ 18 F]acetylhypofluorite afforded, after acidic hydrolysis, 6-[ 18 F]fluoro- l -3,4-dihydroxyphenylalanine (6-FD, 1 ) with a radiochemical yield of 11% (decay corrected and based on the total amount of [ 18 F]F 2 recovered from the target). 6-FD was obtained with a chemical and radiochemical purity of > 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.

In-target production of [13N]ammonia via proton irradiation of dilute aqueous ethanol and acetic acid mixtures.

A reliable, reproducible method has been developed for the in situ production of decicurie quantities of [13N]ammonia by proton irradiation of pressurized, dilute aqueous solutions of acetic acid and ethanol. Some of the parameters investigated for their effect on the 13N product distribution included dose, dose rate, solute concentration, target body material, beam strike volume and proton energy. For the conditions investigated, [13N]NH3 was produced directly in the target in yields greater than 75%.

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.

Proton irradiation of [18O]O2 : Production of [18F]F2, and [18F]F2 +[18F]OF2

The production of 18F electrophilic reagents via the 18O(p,n)18F reaction has been investigated in small-volume target bodies made of aluminum, copper, gold-plated copper and nickel, having straight or conical bore shapes. Three irradiation protocols-single-step, two-step and modified two-step-were used for the recovery of the 18F activity. The single-step irradiation protocol was tested in all the target bodies. Based on the single-step performance, aluminum targets were utilized extensively in the investigation of the two-step and modified two-step irradiation protocols. With an 11-MeV cyclotron and using the two-step irradiation protocol, > 1Ci [18F]F2 was recovered reproducibly from an aluminum target body. Probable radical mechanisms for the formation of OF2 and FONO2 (fluorine nitrate) in the single-step and modified two-step targets are proposed based on the amount of ozone generated and the nitrogen impurity present in the target gases, respectively.

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.

Efficient conversion of 1-aryl-3, 3-dialkyltriazenes to phenols and oxygen-18 labeled phenols

Abstract Phenols have been synthesized in excellent yields using a cation exchange resin (H + form) assisted decomposition of 1-aryl-3,3-dialkyltriazanes in the presence of water. This method is also amenable to a high yield and high enrichment synthesis of oxygen-17 and 18 labeled phenols.

Metals suitable for fluorine gas target bodies: First use of aluminum for the production of [18F]F2☆

A comprehensive evaluation of different metals (aluminum, silver, copper, nickel, and gold-plated copper) was undertaken for the fabrication of target bodies with straight and conical bore shapes for the production of [18F]F2 via the 20Ne(d,alpha)18F nuclear reaction. Of these metals, aluminum, silver and copper have never been used for the production of [18F]F2. All these target bodies were easily passivated using a mild beam-induced plasma technique in the presence of 1% F2 in neon or argon. The recovery of 18F activity was higher with electroformed nickel and silver bodies, probably due to favorable thermal conductivities. Aluminum proved to be a useful material for fluorine gas targets. The consistent recovery of 18F activities, ease and low cost of manufacturing and low nuclear activation properties all make aluminum an ideal choice for fluorine gas targetry. To our knowledge, this investigation is the first to highlight the use of aluminum as a target body material for the routine production of [18F]F2. A reasonable mechanism based on the Langmuir-Rideal surface atom recombination is also proposed for the behavior of [18F]F2 recovery from a nickel target body.

Chemical reactivity of the 18F electrophilic reagents from the 18O(p,n)18F gas target systems

A comprehensive evaluation of the reactivity of 18F electrophilic fluorinating agents derived from the 18O(p,n)18F reaction conducted in target bodies made of aluminum, silver, copper, nickel, and gold-plated copper is reported. Two representative electrophilic reactions, namely addition across a double bond and substitution on an aromatic ring (fluorodemercuration and fluorodestannylation), were tested with the 18F activity generated in the [18O]O2 target systems. Identical reactions were also conducted with analogous nonradioactive fluorinating agents as control experiments. The products of all these reactions were analyzed by NMR spectroscopy. Results of these experiments clearly showed that 18F activities recovered from aluminum, silver, and copper target bodies were better suited for radiochemical syntheses, irrespective of the irradiation protocols employed. The 18F activity from a gold-plated target was suitable only for addition reactions. Further, the fluorodemercuration reaction essentially failed with the single-step irradiation technique conducted in nickel and gold-plated targets. In contrast, the fluorodestannylation reaction was quite successful with the 18F reagents recovered from all the target bodies and irradiation protocols.

High Pressure H2 18O Target for the Production of [18F]Fluoride Ion

Positron emission tomography (PET) plays an important role in clinical research as well as an ever increasing role in the diagnosis and staging of several disease states. The expansion of PET will demand the production of greater quantities of short-lived radiopharmaceuticals and thus the need for increased isotope production. In order to meet the supply needs of the PET community, new methods must be developed to economically achieve the required quantities of short-lived isotopes using the current in-house isotope production equipment (cyclotrons, accelerators) or low cost, low energy accelerators.

Identification and quantitation of gaseous compounds of fluorine generated in [18F]F2 target systems

The first direct evidence for the chemical identity of the electrophilic fluorinating agents generated in 20Ne(d, alpha)18F (single-step), 18O(p,n)18F (single-step and two-step) and 16O(3He2+, p)18F (single-step) gas target systems, utilizing aluminum, silver, copper, nickel and gold plated copper target bodies, has been established with multinuclear NMR and mass spectral techniques. The major components of the reactive fraction from these targets were also quantitated using 19F NMR. Fluorine-19 NMR data of the reactive fraction of all proton and 3He2+ irradiated oxygen gas target systems showed the presence of oxygen difluoride in various proportions. Samples from the single-step method contained up to 20% OF2 while those from the two-step process had 0-5%. Fluorine nitrate (FONO2) was observed only as a minor component (0-3%) in the reactive fraction. The presence of OF2 and FONO2 was further confirmed by 17O and 15N NMR, respectively, using [17O]O2 and [15N]N2 spiked oxygen gas targets. The NMR results were supported by mass spectral data collected with a residual gas analyzer (RGA). Both 19F NMR and mass spectroscopy showed CF4 as the only major inert component in the single-step oxygen target products. As expected, the 19F NMR and mass spectral data showed that the reactive fraction of the neon gas target constituted only F2 and the inert fraction comprised of CF4 and NF3.