Synthesis of carbon-11 labeled organic molecules for PET studies.

摘要

We designed a set of model compounds based on the benzamide structure, which is a widely used structural element in drugs and radiotracers (e.g., histone deacetylase (HDAC) inhibitors, [11C]raclopride), to build up the quantitative structure-property relationship (QSPR) as a prediction tool for dynamic modeling of blood-brain barrier (BBB) permeability. Parallel synthesis was performed to provide seven benzamides and the corresponding precursor molecules for high yield C-11 labelling using [11C]methyl iodide and [11C]methyl triflate. PET imaging studies in the female baboon along with collecting blood samples over a scan time of 60 min revealed high brain uptake and rapid washout. Kinetic modeling enabled the calculation of pharmacokinetic properties of this series of benzamides and their relationship to physicochemical properties and to BBB penetration.;Auxins are important plant hormones that play an essential role in plant growth and development. Indole-3-acetic acid (IAA) is the most common and potent among naturally occurring auxins. Although IAA was structurally characterized in the 1930s, its translocation in the whole plant in response to growth and environmental stimuli is still not completely understood. The development and application of PET radiotracers to probe the auxin biosynthesis pathway, to study sites of auxin biosynthesis, and auxin distribution and metabolism builds on our recent development of tetraethylene glycol promoted two-step, one-pot rapid synthesis of [11C]IAA from [11C]cyanide and its use in studies of root herbivory. Based on this study, routine production of [11C]IAA has become reliable and can be accomplished within 45 -- 50 min in high radiochemical yield and high specific activity for plant studies.;Labeling indole, the first substrate in auxin synthesis, with carbon-11 builds on a new method to incorporate C-11 into ring positions including indole. It can assumed that the ring label will be present in all intermediates in auxin biosynthesis, since indole is a key intermediate in auxin biosynthesis. Accordingly radiolabeling indole allows tracer studies of auxin biosynthesis in vivo in plants. Therefore, we developed a radiosynthesis of [2- 11C]indole via rapid [11C]cyanation followed by reductive cyclization. Our approach involved the reaction of 2-nitrobenzyl bromide with no-carrier-added [11C]cyanide to form [11C]2-nitrophenylacetonitrile followed by reductive cyclization with Raney nickel and hydrazinium monoformate to form [11C]indole. Each step for the synthesis of [2- 11C]indole was fully controlled and systematically optimized to give a high radiochemical yield and high specific activity of [2-11C]indole in 45 minutes. This new radiosynthetic method feeds into studies of signaling molecule biosynthesis and movement in whole plants.;There is evidence that asparagine, similar to glutamine, plays an important role as a nitrogen source in plants. Our objective was to develop a stereospecific synthesis of 11C-labeled L-asparagine, using a five-membered ring sulfamidate precursor and nucleophilic ring-opening with carbon-11 labeled hydrogen cyanide ([11C]HCN) as a radioprecursor. For that, efficient preparation of the cyclic sulfamidate and model reaction without radioisotope (cold chemistry) has been developed. The synthesis of (S)-di-tert-butyl 1,2,3-oxathiazolidine-3,4-dicarboxylate 2,2-dioxide started from commercially available Boc-O-benzyl-L-serine was accomplished in four steps. Based on the success of model reactions in cold chemistry, selective radiosynthesis of L[4-11C]asparagine was accomplished via [11C]cyanation of the sulfamidate followed by hydrolysis with strong acid (TFA/H2SO4) through selective deprotection. Further biological studies via PET imaging are in progress. (Abstract shortened by UMI.).