O. F. Kuznetsova

4-[18F]fluoroglutamic acid (BAY 85-8050), a new amino acid radiotracer for PET imaging of tumors: synthesis and in vitro characterization.

There is a high demand for tumor specific PET tracers in oncology imaging. Besides glucose, certain amino acids also serve as energy sources and anabolic precursors for tumors. Therefore, (18)F-labeled amino acids are interesting probes for tumor specific PET imaging. As glutamine and glutamate play a key role in the adapted intermediary metabolism of tumors, the radiosynthesis of 4-[(18)F]fluoro l-glutamic acid (BAY 85-8050) as a new specific PET tracer was established. Cell-uptake studies revealed specific tumor cell accumulation.

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.

L-[Methyl-(11C)]-methionine of high enantiomeric purity production via online-11C-methylation of L-homocysteine thiolactone hydrochloride

L-[Methyl-(11C)]Methionine ([11C]MET), labelled with carbon-11 (T1/2 = 20 min), is the most commonly used amino acid radiotracer for PET diagnostics of brain tumors. The production of [11C]MET via online11C-methylation of L-homocysteine thiolactone hydrochloride (lactone) on C18 solid phase extraction cartridge creates a problem of insufficient enantiomeric purity (content of L-isomer) of the product. The results of a systematic study of the influence of reaction parameters (lactone/base and the EtOH/H2O ratios, time of 11C-methylation) on the content of L-isomer in the formulation are presented. The developed method of online [11C]MET synthesis allows to obtain a product with a sufficiently high radiochemical yield (75 ± 3%, n = 100, based on [11C]CH3I) and reliably high content of L-isomer (93.7 ± 0.5%) satisfying the requirements of clinical applications. [11C]MET synthesis was performed on a fully automated module designed by the Institute of the Human Brain (IHB RAS).

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.

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.