K. Kawashima

Studies on 18F-labeled pyrimidines

Abstract18F-labeled 5-fluorouracil(FUra), 5-fluoro-2′-deoxyuridine(FdUrd), and 5-fluorouridine(FUrd) were synthesized with high radiochemical purities. The 18F-labeled pyrimidines were injected into rats. The metabolites in serum, bile, and urine were analyzed up to 2 h after administration by radio-high performance liquid chromatography(HPLC). The blood clearance of three pyrimidines was very rapid. In the serum the nucleosides and base disappeared very rapidly with a biological half-life of about 2 min and most of them had disappeared by 60 min. The metabolites in the urine were similar to those in the serum. In the bile pyrimidine nucleosides and base were not detected. 18F was found in the metabolites. Our results explain the high uptakes in the kidney and liver in biodistribution studies of the 18F-labeled pyrimidines.

2-Deoxy-2-[18F]fluoro-d-galactose as an In Vivo tracer for imaging galactose metabolism in tumors with positron emission tomography

The feasibility of 2-deoxy-2-[18F]fluoro-D-galactose ([ 18F]FdGal) for imaging galactose metabolism in tumors with positron emission tomography (PET), was investigated using two hepatomas, Yoshida sarcoma, or glioma in rats, and mouse mammary carcinoma. In hepatoma-bearing rats the highest uptake of [18F]FdGal was observed in the liver followed by the kidney and tumor. The tumor uptake increased with time, and the high uptake ratios of tumor to organ were observed except for the liver and kidney. Tumor uptake was also measured in all tumors. As main metabolites in all tumors, [18F]FdGal 1-phosphate and UDP-[18F]FdGal were found by HPLC. Two hepatomas showed a slightly higher uptake and a larger percentage of UDP derivative than the other three tumors. By autoradiography the brain tumor was visualized clearly. These results indicate that [18F]FdGal has potential as a tracer for imaging galactose metabolism in tumors with PET.

Synthesis of ω-[18F]fluoroalkyl analogs of YM-09151-2 for the measurement of D2-dopamine receptors with PET

Two [18F]fluoroalkyl analogs of a neuroleptic YM-09151-2 were synthesized via nucleophilic [18F]fluorination of methanesulfonyloxy- or p-toluenesulfonyloxyalkyl derivatives using no-carrier-added [18F]fluoride. Although 3-[18F]fluoropropylaminobenzamide was obtained in good yield, the yield of 2-[18F]fluoroethyl derivative was severalfold lower. The product, N-[(2RS,3RS)-1-benzyl-2-methylpyrrolidin-3-yl]-5- chloro-2-methoxy-4-(3-[18F]fluoropropyl)-aminobenzamide, was shown to have a striatum-to-cerebellum ratio comparable to that of 11C labeled YM-09151-2 and thus to be a good candidate for measuring D2-receptors in vivo.

Synthesis and biodistribution of [11C]fludiazepam for imaging benzodiazepine receptors

As a tracer for in vivo studies on benzodiazepine receptors, 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-1-[11C]methyl-2H-1,4- benzodiazepin-2-one, [11C]fludiazepam, was synthesized by the methylation of nor-derivative with [11C]CH3I, and purified by high-performance liquid chromatography. Within 60 min [11C]fludiazepam was obtained for injection in high radiochemical yields and in high radiochemical purity with a specific activity of up to 230 mCi/mumol. After i.v. injection of [11C]fludiazepam in rats the radioactivity was rapidly incorporated into many tissues and the blood clearance of the radioactivity was very rapid. The brain uptake was high and decreased gradually. The adrenal uptake was the highest and decreased with high loading doses. The effect of the loading dose on the uptake was also found in the heart and lungs. By autoradiography using [11C]fludiazepam, a higher accumulation was visualized in the cortex and thalamus than in other regions.

Simplified Enzymatic Synthesis and Biodistribution of 11C-S-Adenosyl-L-Methionine

Abstract11C-S-Adenosyl-l-methionine (11C-SAM) was synthesized enzymatically from 11C-l-methionine using ratliver extract [40%–50% saturated (NH4)2SO4 fraction] as the enzyme source. In biodistribution studies in rats, the highest uptake of 11C-SAM was found in the kidneys. 11C-SAM was also accumulated in the small intestine, pancreas, adrenal gland, liver, and spleen. The uptake of 11C-SAM in the brain increased with time, but remained low. At 30 min after injection, about 50%–60% of the 11C radioactivity was present in the acid-insoluble fraction of the kidneys and liver. When a high loading dose of 11C-SAM was administered, the kidney uptake was enhanced, but the proportion of the radioactivity present in the acid-insoluble fraction was lower. In a study of one rabbit, the kidney uptake was of 11-SAM clearly visualized using positronemission tomography.

11C-coenzyme Q10: a new myocardial imaging tracer for positron emission tomography

Coenzyme Q10 (CoQ10) is a co-factor of the mitochondrial electron-transfer system. 11C-Labeled CoQ10 was synthesized and its biodistribution in rats was examined comparing two kinds of preparation methods using different emulsifiers as a basic study for application of positron emission tomography. 11C-CoQ10 emulsified in saline with polyoxyethylene hydrogenated caster oil was present in the highest concentration in the blood at 30 min. On the other hand, the 11C-CoQ10 emulsified with phospholipids was rapidly cleared from the blood. The liver and spleen uptakes were high probably due to endocytosis, reflecting the characteristics of liposomes. The myocardial uptake was also high just after administration, and the heart-to-blood concentration ratio was over 10 after 5 min. These results suggest that 11C-CoQ10 prepared with liposomes may be a myocardial imaging tracer.

Activation autoradiography: imaging and quantitative determination of endogenous and exogenous oxygen in the rat brain

Endogenous and exogenous oxygen in the rat brain were quantitatively determined using an autoradiographic technique. The oxygen images of frozen and dried rat brain sections were obtained as 18F images by using the 16O (3He,p)18F reaction for endogenous 16O images and the 18O(p,n)18F reaction for endogenous and exogenous 18O images. These autoradiograms demonstrated the different distribution of oxygen between gray and white matter. These images also allowed differentiation of the individual structures of hippocampal formation, owing to the differing water content of the various structures. Local oxygen contents were quantitatively determined from autoradiograms of brain sections and standard sections with known oxygen contents. The estimated values were 75.6 ± 4.6 wt% in gray matter and 72.2 ± 4.0 wt% in white matter. The systematic error in the present method was estimated to be 4.9%.