Synthesis of 18F-labeled streptozotocin derivatives and an in-vivo kinetics study using positron emission tomography.

Glucose transporter 2 (GLUT2) is involved in glucose uptake by hepatocytes, pancreatic beta cells, and absorptive cells in the intestine and proximal tubules in the kidney. Pancreatic GLUT2 also plays an important role in the mechanism of glucose-stimulated insulin secretion. In this study, novel Fluorine-18-labeled streptozotocin (STZ) derivatives were synthesized to serve as glycoside analogs for in-vivo GLUT2 imaging. Fluorine was introduced to hexyl groups at the 3'-positions of the compounds, and we aimed to synthesize compounds that were more stable than STZ. The nitroso derivatives exhibited relatively good stability during purification and purity analysis after radiosynthesis. We then evaluated the compounds in PET imaging and ex-vivo biodistribution studies. We observed high levels of radioactivity in the liver and kidney, which indicated accumulation in these organs within 5 min of administration. In contrast, the denitroso derivatives accumulated only in the kidney and bladder shortly after administration. Compounds with nitroso groups are thus expected to accumulate in GLUT2-expressing organs, and the presence of a nitroso group is essential for in-vivo GLUT2 imaging.

Ethylidene glucose-substituted new analogue of streptozotocin cannot induce diabetes: study on the basis of structure and activity relationship.

4,6-O-Ethylidene glucose (ethylidene glucose), a specific inhibitor at the outer surface of a glucose transporter in the cell membranes, substituted analogue of streptozotocin was newly synthesized. This compound did not induce diabetes in rats and also did not show cytotoxic effect on pancreatic beta cells of neonatal rats in a monolayer culture system. The reasons why such a molecule was designed and why it showed no biological effects are discussed on the basis of a structure-activity relationship. Our results afford positive evidence for the presence of a glucose transport system or a glucose transporter on pancreatic beta cells and its involvement in the action of streptozotocin on beta cells.

Activated N-nitrosocarbamates for regioselective synthesis of N-nitrosoureas.

A practical and convenient method for synthesizing antitumor compounds, N-alkyl-N-nitrosoureas, regioselectively nitrosated on the nitrogen atom bearing the alkyl group is proposed. N-Alkyl-N-nitrosocarbamates are interesting intermediates in these syntheses and yield, by reaction with amino compounds, the regioselectively nitrosated N-alkyl-N-nitrosoureas. As an interesting example, N,N'-bis[(2-chloroethyl)nitrosocarbamoyl]cystamine, a new attractive oncostatic derivative, has been prepared. The cytotoxic activity of these various compounds were tested on L1210 leukemia.

L-Chlorozotocin.

L-Chlorozotocin (2-[[[2-chloroethyl)nitrosoamino]carbonyl]amino]-2-deoxy-L-glucose) was synthesized in seven steps from L-arabinose for comparison with chlorozotocin, which is the D enantiomorph and an antineoplastic agent with clinical potential. Purification of the intermediate 2-amino-2-deoxy-L-glucose as the Schiff's base formed with 4-methoxybenzaldehyde ensured complete separation from the manno epimer. Comparative screening against leukemia L1210 with concurrent toxicity controls revealed no significant difference between D- and L-chlorozotocin in either activity or toxicity.

Analogs and conversion products of streptozotocin.

Reduction of the nitroso group in streptozotocin (1a) has led to cyclized products rather than a semicarbazide (1c). Some analogs (1e, 9a, 9b, 9c and 9d) of streptozotocin in which the nitroso group was replaced by other groups have been prepared.

Alkyl streptozotocin analogues with improved biological activities.

Alkyl 16alpha- and -beta-glycosides of a series of N3-alkyl homologues of streptozotocin were synthesized from glucosamine hydrochloride. These compounds, when tested against ascites Sarcoma 180, Ehrlich ascites carcinoma, or leukemia L1210, exhibited potent antitumor activities, and antibacterial and diabetogenic activities were eliminated. Furthermore, the acute toxicities of these compounds were lower than that of streptozotocin. The methyl, ethyl, n-propyl, and n-butyl glycosides of streptozotocin, whether alpha- or beta-anomers, all showed higher antitumor activities than streptozotocin itself. The most active compound was found to be the methyl beta-streptozotocin.

The synthesis of [14C] streptozotocin and its distribution and excretion in the rat.

[(14)C]Streptozotocin was synthesized specifically labelled at three positions in the molecule. The biological activity of synthetic streptozotocin was characterised by studies in vivo of its diabetogenic activity and its dose-response curves. After this characterization the excretion pattern of all three labelled forms of streptozotocin was studied. With [1-(14)C]streptozotocin and [2'-(14)C]streptozotocin the injected radioactivity was excreted (approx. 70% and 80% respectively) mainly in the urine, the greater part of the excretion occurring in the first 6h period; small amounts (approx. 9% and 8% respectively) were found in the faeces. In contrast, with [3'-methyl-(14)C]streptozotocin a much smaller proportion (approx. 42%) of the injected radioactivity was excreted in the urine, the major proportion appearing in the first 6h, whereas approx. 53% of the injected radioactivity was retained in the carcasses. In whole-body radioautographic studies very rapid renal clearance and hepatic accumulation of the injected radioactivity was observed with all three labelled forms of the drug. There was some evidence for biliary and intestinal excretion. Major differences were apparent in the tissue-distribution studies, with each of the three labelled forms, particularly with [3'-methyl-(14)C]streptozotocin. There was no accumulation of [1-(14)C]streptozotocin in the pancreas for the 6h period after administration. However, with [3'-methyl-(14)C]streptozotocin (and also [2'-(14)C]streptozotocin) there was evidence of some pancreatic accumulation after 2h. The results indicate that streptozotocin is subjected to considerable metabolic transformation and to rapid renal clearance. The implication of these suggestions is evaluated with particular reference to the diabetogenic action of streptozotocin.