Synthesis and preliminary evaluation of (S)-(2-[18F]fluoro-4,5-dihydroxyphenyl)-2-methyl L-alanine, (S)-[18F]-FMEDOPA, a potentially improved imaging agent for the presynaptic dopaminergic nervous system.

The synthesis and preliminary rat biodistribution studies of (S)-(2-[18F]fluoro-4,5-dihydroxyphenyl)-2-methyl L-alanine, (S)-[18F]-FMEDOPA, a potentially improved imaging agent for the presynaptic dopaminergic nervous system, are reported. (S)-[18F]-FMEDOPA produces a higher striatum-to-cerebellum (S/C) radioactivity ratio than the currently used PET imaging agent, (S)-[18F]-FDOPA, does at 180 min after administration.

Nitroxyl analogs as inhibitors of aldehyde dehydrogenase. C-nitroso compounds.

We previously postulated that the catalase-mediated oxidation of cyanamide leads to the formation of the unstable intermediate, N-hydroxycyanamide, which spontaneously decomposes to nitroxyl, the putative inhibitor of aldehyde dehydrogenase (EC 1.2.1.3; AlDH). Since it was not possible to provide direct evidence for the inhibition of AlDH by nitroxyl, we examined the activity of three representative substituted nitroxyls (C-nitroso compounds), viz. nitrosobenzene (NB), 1-nitrosoadamantane (NA), and 2-methyl-2-nitrosopropane (MNP), as direct inhibitors of yeast AlDH in vitro. While NB and NA were highly effective inhibitors in this system exhibiting IC50 values of 2.5 and 8.6 microM, respectively, MNP was considerably less effective with an IC50 of 0.15 mM. When tested in vivo, NA did not show any inhibitory activity on the hepatic AlDH, possibly due to the lack of site-specific delivery of the active monomeric form of this compound. However, NB at a low dose did inhibit hepatic AlDH as reflected by an increase in blood acetaldehyde levels. These results attest to the abilities of NB and NA to act as direct inhibitors of AlDH analogous to nitroxyl itself.

Effects of prolonged oral treatment with N-fluoren-4-ylacetohydroxamic acid on rat liver fine structure.

Inbred male Leeds strain rats were given a diet containing 0.05% N-fluoren-4-ylacetohydroxamic acid for up to 7 months. A modified method for the synthesis of this compound is described. Rats were killed at intervals during and after treatment and their liver tissues examined by light and electron microscopy. The treated rats developed a very low incidence of (non-hepatic) tumours and hepatic clear cell foci appeared during the late stages of the experiment. The only significant fine structural changes observed were glycogenosis and alterations in the morphology of the rough endoplasmic reticulum, both of which developed only after prolonged treatment and affected a minority of hepatocytes. These changes are discussed in relation to the fine structural changes elicited by the strongly carcinogenic N-fluoren-2-ylacetamide and the non-carcinogen, N-fluoren-4-ylacetamide.

Resolution of (+/-)-propranolol.

Two improvements in propranolol resolution were developed. Both the (+)- and (-)-di-(p-toluoyl)tartaric acids were used as the resolving agents. This procedure reduced the number of crystallizations needed to obtain a pure product. Furthermore, synthesis of the resolving agent was improved.

The carcinogenicity of fluorenylhydroxamic acids and N-acetoxy-N-fluorenylacetamides for the rat as related to the reactivity of the esters toward nucleophiles.

In extension of previous work indicating that the carcinogenicity of isomeric fluorenylhydroxamic acids depends on the point of attachment of the nitrogen atom on the fluorene system, the carcinogenicities of N-hydroxy-3-fluorenylacetamide and of N-hydroxy-4-fluorenylacetamide were evaluated in male and female Sprague-Dawley rats by several routes of administration and were compared with the carcinogenicity of N-hydroxy-2-fluorenylacetamide. The earlier observation that N-hydroxy-3-fluorenylacetamide is a specific mamary carcinogen was confirmed. N-Hydroxy-4-fluorenylacetamide was only marginally carcinogenic. Neither isomer gave tumors at the site after i.m. administration of the compounds into the hind leg of the rat. A comparison of the carcinogenicity of the isomers indicated the following order of activity: N-Hydroxy-2-fluorenylacetamide greater than N-hydroxy-3-fluorenylacetamide greater than N-hydroxy-4-fluorenylacetamide. Because of the current concept that arylhydroxamic acids are further acitvated to electrophilic reactants capable of interacting covalently with cellular nucleophiles and because esters of N-hydroxy-2-fluorenylacetamide give rise to an electrophilic reactant, the acetate esters of N-hydroxy-3-fluorenylacetamide and N-hydroxy-4-fluorenylacetamide were prepared and tested for their carcinogenicity in male and female Spaguw-Dawley rats by i.p. and i.m. administration. The order of carcinogenicity of the isomeric esters followed that of the parent hydroxamic acids (N-acetoxy-2-fluorenylacetamide greater than N-acetoxy-3-fluorenylacetamide greater than N-acetoxy-4-fluorenylacetamide). In order to correlate the carcinogeniciyt of the isomeric esters with their reactivity toward nucleophiles, the esters were reacted with methionine, transfer RNA, and the nucleosides, guanosine and adenosine. Under identical conditions, the reactivity of N-acetoxy-2-fluorenylacetamide towards methionine was at least tenfold greater than that of N-acetoxy-4-fluorenylacetamide. In addition to o-methylthio-2-fluorenylacemide, a new adduct, o-methylsulfoxo-2-fluorenylacetamide, was isolated from the reaction of N-acetoxy-2-fluorenylacetamide with methionine. Reaction of N-acetoxy-4-fluorenylacetamide and 1-methylthio-4-fluorenylacetamide. N-Acetoxy-3-fluorenylacetamide did not react with methionine. Continued.