37 research outputs found
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11CO2 Fixation: A Renaissance in PET Radiochemistry
Carbon-11 labelled carbon dioxide is the cyclotron-generated feedstock reagent for most positron emission tomography (PET) tracers using this radionuclide. Most carbon-11 labels, however, are installed using derivative reagents generated from [11C]CO2. In recent years, [11C]CO2 has seen a revival in applications for the direct incorporation of carbon-11 into functional groups such as ureas, carbamates, oxazolidinones, carboxylic acids, esters, and amides. This review summarizes classical [11C]CO2 fixation strategies using organometallic reagents and then focuses on newly developed methods that employ strong organic bases to reversibly capture [11C]CO2 into solution, thereby enabling highly functionalized labelled compounds to be prepared. Labelled compounds and radiopharmaceuticals that have been translated to the clinic are highlighted.Chemistry and Chemical Biolog
The histone H3.1 variant regulates TONSOKU-mediated DNA repair during replication
The tail of replication-dependent histone H3.1 varies from that of replication-independent H3.3 at the amino acid located at position 31 in plants and animals, but no function has been assigned to this residue to demonstrate a unique and conserved role for H3.1 during replication. Here, we show that TONSOKU (TSK/TONSL), which rescues broken replication forks, specifically interacts with H3.1 via recognition of alanine 31 by its tetratricopeptide repeat domain. Our results indicate that genomic instability in the absence of ATXR5/ATXR6-catalyzed H3K27me1 in plants depends on H3.1, TSK and DNA polymerase theta (Pol Ξ). Overall, this work reveals an H3.1-specific function during replication and the common strategy used in multicellular eukaryotes for regulating post-replicative chromatin maturation and TSK, which relies on histone mono-methyltransferases and reading the H3.1 variant
Stereoselective 11C Labeling of a âNativeâ Tetrapeptide by Using Asymmetric Phase-Transfer Catalyzed Alkylation Reactions
The first 11C-labeled unmodified (ânativeâ) peptide is described by alkylation of a tetrapeptide Schiff base, which was achieved by an automated five-step radiochemical reaction. In a proof-of-concept study, [11C]Phe-d-Trp-Lys-Thr was synthesized. This tetrapeptide is the essential pharmacophore of octreotide, an antagonist of somatostatin receptors. The asymmetric alkylation with chiral phase-transfer catalysts enabled direct labeling of a variety of isolated 11C-peptides in a highly stereoselective manner (94 % de) with acceptable radiochemical yields (9â10 %) and practical specific activities (15â35 GBq ”molâ1 or 405â945 mCi ”molâ1) at the end of synthesis. This novel methodology provides a powerful new radiosynthetic method to access novel, stereochemically pure carbon-11-labeled native small peptides ready for in vivo studies
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PET Imaging of Fatty Acid Amide Hydrolase with [18F]DOPP in Nonhuman Primates
Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [11C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [18F]DOPP ([18F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising 18F-labeled analogue based on rodent studies. The goal of this work is to evaluate [18F]DOPP in nonhuman primates to support its clinical translation. High specific activity [18F]DOPP (5â6 Ci·Όmolâ1) was administered intravenously (iv) to three baboons (2M/1F, 3â4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 ÎŒg/kg iv, 10 min prior to [18F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated âŒ95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [18F]DOPP covalently links to the active site of FAAH. Consistent with previous findings for [11C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter λk3 was therefore used to evaluate whole brain (WB) and regional binding of [18F]DOPP. Pretreatment studies showed inhibition of λk3 across all brain regions (WB baseline: 0.112 mL/cm3/min; 300 ÎŒg/kg URB597: 0.058 mL/cm3/min), suggesting that [18F]DOPP binding is specific for FAAH, consistent with previous rodent data
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Synthesis of [ 11 C]Bexarotene by Cu-Mediated [ 11 C]Carbon Dioxide Fixation and Preliminary PET Imaging
Chemistry and Chemical Biolog
Shifting the Energy Landscape of Multicomponent Reactions Using Aziridine Aldehyde Dimers: A Mechanistic Study
A multicomponent reaction between
an aziridine aldehyde dimer,
isocyanide, and l-proline to afford a chiral piperazinone
was studied to gain insight into the stereodetermining and rate-limiting
steps of the reaction. The stereochemistry of the reaction was found
to be determined by isocyanide addition, while the rate-limiting step
was found to deviate from traditional isocyanide-based multicomponent
reactions. A first-order rate dependence on aziridine aldehyde dimer
and a zero-order rate dependence on all other reagents have been obtained.
Computations at the MPWPW91/6-31GÂ(d) level supported the experimental
kinetic results and provide insight into the overall mechanism and
the factors contributing to stereochemical induction. These factors
are similar to traditional isocyanide-based multicomponent reactions,
such as the Ugi reaction. The computations revealed that selective
formation of a <i>Z</i>-iminium ion plays a key role in
controlling the stereoselectivity of isocyanide addition, and the
carboxylate group of l-proline mediates stereofacial addition.
These conclusions are expected to be applicable to a wide range of
reported stereoselective Ugi reactions and provide a basis for understanding
the related macrocyclization of peptides with aziridine aldehydes
<sup>11</sup>CO bonds made easily for positron emission tomography radiopharmaceuticals
The positron-emitting radionuclide carbon-11 ((11)C, t1/2 = 20.3 min) possesses the unique potential for radiolabeling of any biological, naturally occurring, or synthetic organic molecule for in vivo positron emission tomography (PET) imaging. Carbon-11 is most often incorporated into small molecules by methylation of alcohol, thiol, amine or carboxylic acid precursors using [(11)C]methyl iodide or [(11)C]methyl triflate (generated from [(11)C]carbon dioxide or [(11)C]methane). Consequently, small molecules that lack an easily substituted (11)C-methyl group are often considered to have non-obvious strategies for radiolabeling and require a more customized approach. [(11)C]Carbon dioxide itself, [(11)C]carbon monoxide, [(11)C]cyanide, and [(11)C]phosgene represent alternative reactants to enable (11)C-carbonylation. Methodologies developed for preparation of (11)C-carbonyl groups have had a tremendous impact on the development of novel PET tracers and provided key tools for clinical research. (11)C-Carbonyl radiopharmaceuticals based on labeled carboxylic acids, amides, carbamates and ureas now account for a substantial number of important imaging agents that have seen translation to higher species and clinical research of previously inaccessible targets, which is a testament to the creativity, utility and practicality of the underlying radiochemistry
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Practical Radiosynthesis and Preclinical Neuroimaging of [11C]isradipine, A Calcium Channel Antagonist
In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·Όmolâ1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 ± 0.08 %ID/cc (percent of injected dose per cubic centimeter) at peak, 15â60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg·kgâ1, i.p.), whole brain radioactivity uptake was diminished by 25â40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned
Practical Radiosynthesis and Preclinical Neuroimaging of [11C]isradipine, a Calcium Channel Antagonist
In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·”molâ1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 ± 0.08% ID/cc (percent of injected dose per cubic centimeter) at peak, 15â60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg·kgâ1, i.p.), whole brain radioactivity uptake was diminished by 25%â40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned
Conformational Modulation of in Vitro Activity of Cyclic RGD Peptides via Aziridine Aldehyde-Driven Macrocyclization Chemistry
Here, we demonstrate a conjugation strategy whereby cyclic
RGD-containing
macrocycles are prepared using aziridine aldehydes, isocyanides, and
linear peptides, followed by conjugation to a cysteamine linker. Our
method involves site-selective aziridine ring-opening with the nucleophilic
sulfhydryl group of cysteamine. Fluorescein was then efficiently conjugated
to the primary amine of cysteamine by NHS-chemistry. This strategy
may be expanded to provide easy access to a wide variety of fluorescent
dyes or radiometal chelators. Modeling studies showed that aziridine
aldehyde cyclization chemistry stabilized the RGD motif into the required
bioactive conformation and that this cyclization chemistry modulated
the geometry of macrocycles of different residue lengths. In vitro
studies showed that cPRGDA and cPRGDAA both selectively bound to α<sub>V</sub>ÎČ<sub>3</sub>-overexpressing U87 glioblastoma cells,
and that cPRGDA had a better binding affinity compared to cPRGDAA.
The improved binding affinity of cPRGDA was attributed to the fixed
Pro-C<sup>α</sup>-Asp-C<sup>α</sup> distance surrounding
the stabilized RGD motif in cPRGDA