Terushi Haradahira

Metabolic pathway of 2-deoxy-2-fluoro-D-glucose studied by F-19 NMR

The behavior of 2-deoxy-2-fluoro-D-glucose (FDG) in mouse has been studied by F-19 NMR method for long period. The F-19 NMR signals of FDG or its metabolites were observed in tissues without serious broadening. FDG was found to be accumulated in organs in the form of FDG or FDG-6-phosphate and 2-deoxy-2-fluoro-D-mannose (FDM) or FDM-6-phosphate, and the latter dominated the former in the heart sampled at 24 hr or later. The fluorine compounds were excreted in urine in both forms. The clearance was rapid from brain, liver, and blood, but was slow from heart.

Synthesis and evaluation of 3-(4-chlorobenzyl)-8-[11C]methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one: a PET tracer for imaging sigma1 receptors

Abstract 3-(4-Chlorobenzyl)-8-methoxy-1,2,3,4-tetrahydrochromeno[3,4- c ]pyridin-5-one (1), a putative dopamine D 4 receptor antagonist (k i = 8.7 nM), was labeled by positron-emitter ( 11 C) and its pharmacological evaluation was carried out with in vitro quantitative autoradiography and positron emission tomography (PET). 11 C-Methylation of a corresponding desmethyl precursor (2) with [ 11 C]CH 3 I gave [ 11 C]1 with ≥98% of radiochemical purity after HPLC purification and 67–90 GBq/μmol of specific activity at the end of synthesis. The in vitro autoradiography using rat brain sections demonstrated that [ 11 C]1 shows no specific binding to the D 4 receptors, but a high specific binding to sigma 1 receptors (IC 50 = 105 nM). In the PET study with monkey brain, [ 11 C]1 was highly taken up by the brain and trapped in the brain for at least 90 min. The distribution pattern of radioactivity in the brain was striatum > thalamus > frontal cortex > cerebellum, which was same as the result of in vitro autoradiography. Pre-treatment with non-radioactive 1 (1 mg/kg) produced a significant reduction of radioactivity in all the regions including the cerebellum. Pre-treatment with (+)pentazocine (1 mg/kg), a selective σ 1 receptor agonist, also reduced the radioactivity in the same regions to a similar extent. These results indicate that [ 11 C]1 may have some specific binding to the sigma 1 receptors, which is consistent with the result of in vitro autoradiography.

Radiosynthesis, rodent biodistribution, and metabolism of 1-deoxy-1-[18F]fluoro-d-fructose

Fluorine-18 labeled analog of D-fructose, 1-deoxy-1-[18F]fluoro-D- fructose (1-[18F]FDFrc), was synthesized by nucleophilic substitution of [18F]fluoride ion and the effect of the fluorine substitution on its in vivo metabolism was investigated. The tissue distributions of 1-[18F]FDFrc in rats and tumor bearing mice showed initial high uptake and subsequent rapid washout of the radioactivity in the principal sites of D-fructose metabolism (kidneys, liver and small intestine). The uptakes in the brain and tumor (fibrosarcoma) were the lowest and moderate, respectively, but tended to increase with time. The in vivo metabolic studies of 1-[18F]FDFrc and nonradioactive 1-FDFrc in mouse brain and tumor showed that the fluorinated analog remained unmetabolized in these tissues, indicating that the substitution of fluorine at the C-1 position produces a nonmetabolizable analog of D-fructose. Thus, 1-[18F]FDFrc had no features of a metabolic trapping tracer without showing any appreciable organ or tumor specific localization.

Synthesis and biodistribution of a fluorine-18 labeled analogue of D-talose: 2-deoxy-2-[18F]fluoro-D-talose.

A fluorine-18 labeled analogue of D-talose, 2-deoxy-2-[18F]fluoro-D-talose ([18F]FDT), was synthesized via nucleophilic fluorination with [18F]fluoride ion and its biodistributions in animals were examined. Radiofluorination of benzyl 3,5,6-tri-O-benzyl-2-O-(trifluoromethanesulfonyl)-alpha-D-galac tof uranoside (5) with aminopolyether supported potassium [18F]fluoride (K18F/Kry222) in acetonitrile followed by deprotection of the [18F]fluorinated intermediate (6) with boron tribromide in CH2Cl2 gave [18F]FDT in an average radiochemical yield of 29% with a radiochemical purity greater than 98%. Biodistribution studies of [18F]FDT in mice bearing fibrosarcoma showed the highest uptake of radioactivity in the liver (34.9% dose/g), followed by the kidney (15.9%dose/g), the small intestine (12.9%dose/g) and fibrosarcoma (5.7%dose/g), at 30 min after i.v. administration. Although the radioactivity in the kidney and small intestine decreased with time, the uptake in the liver and the tumor slightly increased until 120 min. The high liver uptake of [18F]FDT was also observed in normal rats and this uptake was strongly inhibited by co-administration of D-galactose. These preliminary results suggest that [18F]FDT might be metabolized through the galactose metabolic pathway as analogously observed with 2-deoxy-2-[18F]fluoro-D-galactose which is an isomer with respect to carbon-2 of [18F]FDT, and that it may be another candidate for studying liver function by positron emission tomography.

A new, high yield synthesis of 2-deoxy-2-fluoro-D-glucose

The reaction of 1,6-anhydro-3,4-di-O-benzyl-2-O-(trifluoromethanesulphonyl)-β-D-mannopyranose (4) with tetraalkylammonium fluorides provides a rapid, high yield synthetic route to 2-deoxy-2-fluoro-D-glucose.

Metabolic pathway of 2-deoxy-2-[18F]fluoro-d-talose in Mice: Trapping in tissue after phosphorylation by galactokinase

To make clear the metabolic fate of 2-deoxy-2-[18F]fluoro-D-talose ([18F]FDT) in animals, the in vivo and in vitro metabolism of non-radioactive 2-deoxy-2-fluoro-D-talose (FDT) was investigated by 19F-NMR spectroscopy. Based on the 19F-NMR spectral analyses, 2-deoxy-2-fluoro-alpha-D-talose-1-phosphate (FDT-1-P) was identified as a single metabolite in the organs of tumor-bearing mice after FDT administration (60 mg/kg). In the liver, almost all FDT was converted to FDT-1-P within 10 min after FDT injection and the phosphate form remained unchanged for at least 3 h. FDT was well converted to FDT-1-P by galactokinase in vitro. The FDT-1-P formed, however, failed to convert to a uridylate derivative by treatment with galactose-1-phosphate uridyltransferase. The observed low affinity of galactose-1-phosphate uridyltransferase for the FDT-1-P could account for the accumulation mechanism of FDT-1-P in vivo. Similar metabolic studies of [18F]FDT with radio-TLC demonstrated the [18F]FDT-1-P as a single metabolite of [18F]FDT in the mouse liver. These results indicate that [18F]FDT enters a D-galactose metabolic pathway and undergoes a metabolic trapping in the [18F]FDT-1-P form by galactokinase in the tissues such as liver and tumor. Consequently, [18F]FDT is expected to be a new radiopharmaceutical for the measurement of galactokinase activity by positron emission tomography.