Dedicated to Professor Jürgen Martens on the occasion of his outstanding contribution to organic synthetic chemistry DOI: http://dx.doi.org/10.3998/ark.5550190.p008.802
AbstractEnantioselective construction of a C 2 -symmetric spirobi(1,2,3,4-tetrahydroquinoline) framework has been achieved through an intramolecular Cu-catalyzed C-N bond coupling of 1,3-propanediamide substrates possessing bromophenyl substituents. The use of N,N'-dimethyl-1,2-diphenylethylenediamine as the chiral ligand was found to be essential in this asymmetric catalysis. Optically pure compound was shortly obtained by a single recrystallization of the enantioenriched product, which was successfully derivatised to a new chiral diphosphine ligand.
The efficient synthesis of L-[5-11 C]leucine and L-α-[5-11 C] methylleucine has been investigated using a continuous twostep sequence of rapid reactions consisting of Pd 0 -mediated 11 C-methylation and microfluidic hydrogenation. The synthesis of L-[5-11 C]leucine and L-α-[5-11 C]methylleucine was accomplished within 40 min with a decay-corrected radiochemical yield of 15-38 % based on [ 11 C]CH 3 I, radiochemical purity of 95-99 %, and chemical purity of 95-99 %. The Pd impurities in the injectable solution measured using inductively coupled plasma mass spectrometry met the international criteria for human use. Positron emission tomography scanning after an intravenous injection of L-[5-11 C]leucine or L-α-[5-11 C]methyl leucine in A431 tumor-bearing mice was performed. As a result, L-α-[5-11 C] methylleucine was found to be a potentially useful probe for visualizing the tumor. Tissue distribution analysis showed that the accumulation value of L-α-[5-11 C]methylleucine in tumor tissue was high [12 � 3% injected dose/g tissue (%ID/g)].
Amino acid transporters are upregulated in many cancer
cells, and
system L amino acid transporters (LAT1–4), in particular, LAT1,
which preferentially transports large, neutral, and branched side-chain
amino acids, are considered a primary target for cancer positron emission
tomography (PET) tracer development. Recently, we developed a 11C-labeled leucine analog, l-α-[5-11C]methylleucine ([5-11C]MeLeu), via a continuous two-step
reaction of Pd0-mediated 11C-methylation and
microfluidic hydrogenation. In this study, we evaluated the characteristics
of [5-11C]MeLeu and also compared the sensitivity to brain
tumors and inflammation with l-[11C]methionine
([11C]Met) to determine its potential for brain tumor imaging.
Competitive inhibition experiments, protein incorporation, and cytotoxicity
experiments of [5-11C]MeLeu were performed in vitro. Further,
metabolic analyses of [5-11C]MeLeu were performed using
a thin-layer chromatogram. The accumulation of [5-11C]MeLeu
in tumor and inflamed regions of the brain was compared with [11C]Met and 11C-labeled (S)-ketoprofen
methyl ester by PET imaging, respectively. Transporter assay with
various inhibitors revealed that [5-11C]MeLeu is mainly
transported via system L amino acid transporters, especially LAT1,
into A431 cells. The protein incorporation assay and metabolic assay
in vivo demonstrated that [5-11C]MeLeu was neither used
for protein synthesis nor metabolized. These results indicate that
MeLeu is very stable in vivo. Furthermore, the treatment of A431 cells
with various concentrations of MeLeu did not change their viability,
even at high concentrations (∼10 mM). In brain tumors, the
tumor-to-normal ratio of [5-11C]MeLeu was more elevated
than that of [11C]Met. However, the accumulation levels
of [5-11C]MeLeu were lower than those of [11C]Met (the standardized uptake value (SUV) of [5-11C]MeLeu
and [11C]Met was 0.48 ± 0.08 and 0.63 ± 0.06,
respectively). In brain inflammation, no significant accumulation
of [5-11C]MeLeu was observed at the inflamed brain area.
These data suggested that [5-11C]MeLeu was identified as
a stable and safe agent for PET tracers and could help detect brain
tumors, which overexpress the LAT1 transporter.
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