Marc S. Berridge

An efficient radiosynthesis of [18F]fluoromisonidazole.

An efficient preparation of the hypoxic cell tracer [18F]3-fluoro-1-(2-nitro-1-imidazolyl)-2-propanol ([18F]fluoromisonidazole) is reported. This radiopharmaceutical is of interest to probe hypoxic tissue in infarcts and tumors. One-step radiolabeling and rapid protection group removal provided 55-80% yield in 50 min. The process is similar to common fluorine labeling procedures, simplifying the procedure for most laboratories, and offers an improvement over more difficult previous methods. The labeling precursor was prepared in five steps from readily available materials in a straightforward reaction scheme.

The use of 3-methoxymethyl-16β, 17β-epiestriol-O-cyclic sulfone as the precursor in the synthesis of F-18 16α-fluoroestradiol

Abstract We have prepared 3-methoxymethyl-16β,17β-epiestriol- O -cyclic sulfone (1c) and used it as a substrate for the production of F-18 16α-fluoroestradiol, via nucleophilic fluorination with fluoride ion. The compound is straightforward to make from the commercially available epiestriol and is a stable crystalline compound that can be stored for at least a year at room temperature. Reaction with fluorine-18 fluoride provides excellent yields; typically >90% incorporation of the fluoride is achieved. Partial purification of the labeled product may be accomplished at this stage. Hydrolysis of the methoxymethyl protecting group and ring-opened sulfate occurs rapidly in ethanolic acid solution. In the presence of water the hydrolysis requires more vigorous conditions and additional time but still proceeds to completion. Labeled fluoroestradiol is isolated at the end of a 1–2 h synthesis, depending on the hydrolysis method of 30–45% chemical (decay corrected) yield with respect to fluoride, with a specific activity >1 Ci per micromole.

Synthesis of [18F]fluoromethyl iodide, a synthetic precursor for fluoromethylation of radiopharmaceuticals

[18F]fluoroiodomethane was labeled via nucleophilic substitution of diiodomethane with [18F]fluoride, and labeling conditions were optimized. The optimized labeling yield was 40 +/- 8% (decay-corrected). The synthesis and purification of [18F]fluoroiodomethane took 15 min. The reactions of [18F]fluoroiodomethane with amine, carboxylic acid, thiol and phenoxide groups produced fluoromethylated derivatives with various yields (12-95%). The results indicated that [18F]fluoroiodomethane is a valuable synthetic precursor for the introduction of an [18F]fluoromethyl group into radiopharmaceuticals.

In-target production of [13N]ammonia: Target design, products, and operating parameters

[13N]Ammonia, commonly used in PET, has been prepared in good yield in the target. Up to 800 mCi of radiopharmaceutical was obtained by in-line processing of the irradiated water. Relatively low hydrogen pressure was used to control the target chemistry. Target designs and the product dependence on beam dose, dose rate and pressure are reported. Ethanol as a target additive was also investigated. Hydrogen and ethanol together were more effective than either alone at high beam dose. Parameters are reported for production needs from single doses to synthetic applications. An incidental method for production of [13N]nitrogen gas is also reported.

Designs and use of silver [18O]water targets for [18F]fluoride production

Abstract A series of targets for production of fluorine-18 from enriched [18O]water were constructed using a double-foil design and silver spacers. The final target was provided standard with Scanditronix MC-17 cyclotrons and has been used for many years. Years of operating experience and production data are drawn upon to discuss features of the designs, and also the handling and methods of routine use of a double-foil low-pressure target as they relate to target performance.

Low-carrier production of [15O]oxygen, water and carbon monoxide

Abstract In the course of work to label butanol with 15 O, it became necessary to decrease carrier oxygen levels used in 15 O production. The low carrier conditions are incompatible with widely used techniques for production of labeled water and carbon monoxide. Method modifications are reported for production of these radiopharmaceuticals under low-carrier conditions, including the use of platinum as a catalyst for [ 15 O]water production. With these methods, it is possible to continue to produce all routine 15 O radiopharmaceuticals using a single, low-carrier, target gas.

Preparation and in vivo binding of [11C]carazolol, a radiotracer for the beta-adrenergic receptor

Carazolol is a high affinity beta-adrenergic receptor antagonist which is relatively non-specific for the receptor subtypes. The labeling of the two enantiomers of this compound with carbon-11, including the synthesis of the required labeling precursors, is reported. The yield and specific activity are sufficient for use in positron tomography. Biodistribution and specific receptor binding studies show the labeled material to be of interest for further investigation as a radiopharmaceutical for positron tomography.

Synthesis and properties of 18F-labeled potential myocardial blood flow tracers

PET centers without particle accelerators make clinical PET widely available at reduced cost. For myocardial perfusion tracers, these satellite PET centers are limited to generator- produced 82Rb(+) and 62Cu[PTSM]. Their limitations motivate a search for transportable alternatives. In search of new tracers we have synthesized several 18F-labeled amines and quaternary ammonium salts. Among them, 4-[18F]fluorotri-N-methylanilinium ([18F]FTMA) has flow-tracing properties. The compound is functional, but has properties that justify a continued search.

In vivo characterization of inhaled pharmaceuticals using quantitative positron emission tomography.

R Rorer (RPR) manufactures a number of marketed products containing the active ingredient triamcinolone acetonide (TAA), a potent anti-inflammatory corticosteroid. Intranasal and inhalation formulations containing the active ingredient have been characterized using positron tomography. Studies employing PET (positron emission tomography) technology were designed to fully characterize the in vivo deposition of the active drug in commercial products. Determination of the in vivo deposition provided information needed to address evolving scientific, regulatory, and marketing requirements. These studies were designed to measure the regional delivery patterns of the active ingredient and evaluate the effectiveness of the drug delivery apparatus in depositing the drug onto target tissues. The demand to quantify and obtain a dynamic assessment of the residency of the drug as a function of time at specific target regions was added to provide insights and an explanation for the long duration of effect supported by clinical studies. PET techniques are not new, but the demands of these experimental designs imposed new requirements on data acquisition techniques and on data analysis. Although this effort did not address typical issues related to drug development, the effort has created a powerful tool that will be used to address drug development issues in the future. This brief summary report will highlight finished studies to better assess the impact that these imaging studies have had on practical matters of drug development, evaluation, and marketing. STUDY DESIGNS

High-yield, low-pressure [18O] water targets of titanium and niobium for F-18 production on MC-17 cyclotrons

Large volume low-pressure targets were designed for use on the wide-beam Scanditronix MC-17 cyclotron. The design was optimized experimentally by construction of aluminum test targets. Final production targets were constructed of titanium and niobium. The targets tripled the routine production yield of the previous target, giving up to 90 GBq (2.5 Ci) of fluoride and essentially eliminated the need for periodic target maintenance. The final targets represent a considerable improvement. However, they have not performed as well as predicted, indicating that further improvement is possible.