R. N. Krasikova

Optimization of Automated Synthesis of 2-[18F]Fluoro-2-deoxy-D-glucose Involving Base Hydrolysis

Synthesis of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) involving base hydrolysis was optimized. Fluorine-18 was isolated from irradiated water to more than 90% by sorption of [18F]fluoride on QMA anion-exchange resin, which was followed by elution with a 96 : 4 (by volume) acetonitrile-water mixture containing Kryptofix 2.2.2 and potassium carbonate (molar ratio 2 : 1). This composition is the best for preparing the complex [K/K2.2.2]+18F- used in nucleophilic fluorinations. No additional azeotropic drying is required. Base hydrolysis under optimized conditions (40-45°C), followed by neutralization with HCl, removal of traces of the solvent, and purification of the final product on a combined SCX/Alumina N column, yielded [18F]FDG of high radiochemical (>99%) and chemical purity with minimal product loss. With an RB-86 robotic system (Anatech, Sweden), the synthesis time was 38 min. The procedure is used in the Institute of Human Brain, Russian Academy of Sciences for routine synthesis of FDG; the radiochemical yield of the product by the end of synthesis (EOS) is reproducibly high: 63±3% (n = 40).

Preparation of [18F]Flumazenil, a Potential Radioligand for PET Imaging of Central Benzodiazepine Receptors, by Isotope Exchange

Abstract[18F]Flumazenil was prepared by a new route: isotope exchange of 19F for 18F under standard conditions of nucleophilic fluorination using the complex [K/K2.2.2]+18F-. The radiofluorination efficiency was 62±8% (n = 8) under the following conditions: solvent dimethyl sulfoxide, 5 min, 130°C, flumazenil sample weight 2 mg, and equimolar ratio of potassium cryptate ([K2CO3/K2.2.2]) to flumazenil. Yield of the product after purification by solid-phase exraction on a tC18 column, corrected for 18F decay, 47±3% (n = 5). The identity of [18F]flumazenil was confirmed by radio-HPLC using three different chromatographic systems.

Asymmetric synthesis of 6-18F-L-FDOPA using chiral Nickel(II) complexes

A new procedure was suggested for asymmetric synthesis of of 6-[18F]fluoro-3,4-L-dihydroxyphenylalanine (6-18F-L-FDOPA), an important radiotracer for studies of the dopaminergic system by positron emission tomography (PET). The key step of the synthesis is stochiometric asymmetric alkylation of chiral Ni(II) complexes using 3,4-methylenedioxy-6-[18F]fluorobenzyl bromide as alkylating agent. A series of Ni(II) complexes containing various substituents in the benzyl group were tested. The highest enantiomeric purity of 6-18F-L-FDOPA was attained with the complex derived from (S)-N-(2-benzoylphenyl)-1-(3,4-dichlorobenzyl)-pyrrolidine-2-carboxamide, Ni-DCBPB-Gly, under mild alkylation conditions (CH2Cl2, 40°C, potassium tert-butylate as base). Such conditions are favorable from the viewpoint of synthesis automation. The radiochemical yield of 6-18F-L-FDOPA corrected for the radioactive decay was 10–15% at a synthesis time of 120 min, including purification by semipreparative HPLC. The radiochemical and chemical purity of the product exceeded 99%, and the enantiomeric purity was as high as 95%, meeting the requirements for using 6-18F-L-FDOPA in PET practice.

Radionuclides and radiopharmaceuticals for single-photon emission tomography, positron emission tomography and radiotherapy in Russia.

Abstract. The current status of the manufacture of radiopharmaceuticals for diagnostic and therapeutic application in Russia is discussed, consideration being given to various aspects of the production and distribution of radionuclides, radioisotope generators and kits as well as individual radiopharmaceuticals in different regions of the country. The major focus is on the recent developments in production technologies for therapeutic and single-photon emission tomography radionuclides, technetium chemistry and synthetic approaches for the labelling of compounds with short-lived positron emitters. The status of positron emission tomography and its application are considered. The major factors restricting the expansion of nuclear imaging techniques and radiotherapy in Russia are also discussed.

Use of 2-[18F]fluoroethyl bromide in synthesis of O-(2′-[18F]fluoroethyl)-L-tyrosine, a radiotracer for PET diagnostics of brain tumors

The possibility of using 2-[18F]fluoroethyl bromide ([18F]FEB) as labeled reagent for selective O-[18F]fluoroethylation of phenolic group in the presence of an unprotected amino group in an amino acid molecule was demonstrated by the example of the synthesis of O-(2′-[18F]fluoroethyl)-L-tyrosine ([18F]FET), one of the most promising PET radiotracers for evaluating the rate of transport of amino acids into a tumor tissue. The labeled reagent was prepared by [18F]fluorination of 2-bromoethyl tosylate with the complex [K/K2.2.2]/[18F] in o-dichlorobenzene (110°C, 10 min) and was transferred with a nitrogen flow into a solution of the substrate (L-tyrosine, NaOH, dimethyl sulfoxide or dimethyl sulfoxide/o-dichlorobenzene). The reaction with the substrate was performed for 20 min at 100°C; the degree of O-[18F]fluoroethylation was 75%. [18F]FET was prepared with a high radiochemical purity (>95%); the total synthesis time, including HPLC purification, was 60 min, and the unoptimized radiochemical yield (corrected for the radioactive decay) was about 20%. The synthesis was performed with an Anatech RB-86 laboratory robot.

Synthesis of 2-[18F]Fluoro-L-tyrosine and comparative study of its uptake by rat glioma 35 tumor and by induced inflammation focus in experimental animals

Abstract2-[18F]Fluoro-L-tyrosine (2-[18F]FTYR), a labeled fluorinated analog of tyrosine, was prepared using chiral phase-transfer catalysis. The radiochemical yield of 2-[18F]FTYR corrected for radioactive decay was 25±6% (n = 15) at a synthesis time of 110–120 min, including semipreparative HPLC purification. The radiochemical and chemical purity of the product exceeded 99%, and the enantiomeric purity was 98.2±0.7% (n = 15). The uptake of 2-[18F]FTYR by tumors and abscesses in laboratory animals was studied. The ratios of radioactivity uptake by tumor or imflamed tissue to that of an intact muscle tissue were calculated. Within the time of experiment, the tumor/muscle ratio exceeds the abscess/muscle ratio. The results obtained allow 2-[18F]FTYR to be considered as potentially useful radiotracer for differential diagnostics of tumors and inflammations by PET.

A fast and convenient method for robotic preparation of [11C]flumazenil avoiding HPLC purification

A new approach for robotic preparation of [11C]flumazenil with recovery of the final product by SPE technique has been developed. A hydrogen-bond-assisted methylation in a suspension of potassium fluoride absorbed on alumina was followed by purification using a standard Sep-Pak Neutral Alum N Light cartridge. As a result, the contamination of the final product with its precursor Ro 15-5528 was reduced to similar levels as obtained by traditional semi-preparative HPLC. The synthesis of [11C]flumazenil was operated by the commercially available robot Anatech RB-86. The formulated solution of [11C]flumazenil was obtained within 18 min starting from trapping of [11C]methyl iodide. The simplicity of this method and the use of disposable materials for purification instead of HPLC may be advantageous for routine clinical use. Copyright

18F-labeled tyrosine derivatives: Synthesis and experimental studies on accumulation in tumors and abscesses

Tyrosine derivatives labeled with a short-lived fluorine-18 isotope (T1/2 110 min), namely 2-[18F]fluoro-L-tyrosine (FTYR) and O-(2′-[18F]fluoroethyl)-L-tyrosine (FET), promising radiopharmaceuticals (RPs) for positron emission tomography (PET), were obtained by asymmetric syntheses. Accumulation of FTYR and FET in the rat tumor “Glioma 35 rats tumor” and in abscesses induced in Wistar rats muscles was studied and compared with that of a well-known glycolysis radiotracer 2-[18F]fluoro-2-deoxy-D-glucose (FDG). It was shown that the relative accumulation indices of amino acid RPs were considerably lower than those of FDG. At the same time, tumor/muscle ratios were high enough (2.9 for FET and 3.9 for FTYR 120 min after injection) for reliable tumor visualization. The data obtained indicated a possibility in principle to use FTYR and FET for differentiated PET diagnostics of brain tumors and inflammation lesions. Of the tyrosine derivatives studied, FET seems to be the most promising agent due to a simple and easily automated method of preparation based on direct nucleophilic substitution of the leaving tosyloxy group of an enantiomerically pure Ni-(S)-BPS-(S)-Tyr(CH2CH2OTs) precursor by an activated [18F]fluoride.

Preparation and Quality Control of [N-Methyl-11C]choline for Routine PET Application

The goal of this study was to optimize the synthesis of [N-methyl-11C]choline, a radiopharmaceutical used in the diagnosis of brain tumors and prostate cancer with positron emission tomography (PET). The synthetic method is based on methylation with [11C]CH3I of N,N-dimethylaminoethanol (DMAE) immobilized on the surface of a tC18 solid support (Waters). The optimal amounts of DMAE (25 μl in 50 μl of ethanol) and tC18 (0.1 g) were found, providing a high radiochemical yield of the labeled choline (85%, corrected for radioactive decay) and radiochemical purity of more than 99.5%. After purification on the Sep-Pak Light cation-exchange cartridge (Accell Plus CM, Waters), the concentration of DMAE in the final product was 1.6 μg ml-1. For monitoring of DMAE in the final product, a simple and convenient HPLC method with an indirect UV detection providing sufficient sensitivity was proposed.

Prepatation of [18F]Fluorobenzyl Bromides for Their Use in Asymmetric Synthesis of Fluorinated α-Amino Acids, Radiotracers for Positron Emission Tomography

Procedures were developed for synthesis of 3,4-methylenedioxy-6-[18F]fluorobenzyl bromide I and 2-[18F]fluoro-4-methoxybenzyl bromide Ia, which are intermediates in asymmetric synthesis of fluorinated α-amino acids used in positron emission tomography (PET). The bromination procedures involving two brominating agents, an ethereal solution of HBr or triphenyldibromophosphorane in various solvents, as well as purification procedures, were compared. An optimized procedure was suggested for synthesis of I and Ia using an Anatech robotic system; the total synthesis time is 45-48 min. The radiochemical yield of I and Ia, corrected for the 18F decay, was 35-40 and 60-65%, respectively. The suggested scheme can be adapted to modern automated modules for production of radiopharmaceuticals.