Journal of labelled compounds & radiopharmaceuticals最新文献

CuI-mediated ¹¹C-cyanation was evaluated by synthesizing [¹¹C]perampanel ([¹¹C]5) as a model compound and compared with previous reports. To a DMF solution with 5′-(2-bromophenyl)-1′-phenyl-[2,3′-bipyridin]-6′(1′H)-one (4) and CuI, [¹¹C]NH₄CN in a stream of ammonia/nitrogen (5:95, v/v) gas was bubbled. Subsequently, the reaction mixture was heated at 180°C for 5 min. After HPLC purification, [¹¹C]5 was obtained in 7.2 ± 1.0% (n = 4) non-decay corrected radiochemical yield with >99% radiochemical purity and a molar activity of 98 ± 28 GBq/μmol. In vivo evaluations of [¹¹C]5 were performed using small animals. PET scans to check the kinetics of [¹¹C]5 in the whole body of mice suggested that [¹¹C]5 spreads rapidly into the brain, heart, and lungs and then accumulates in the small intestine. To evaluate the performance of CuI-mediated ¹¹C-cyanation reaction, bromobenzene (6a) was selected as the model compound; however, it failed. Therefore, optimization of the reaction conditions has been performed, and consequently, the addition of K₂CO₃ and prolonging the reaction time improved the radiochemical yield about double. With this improved method, CuI-mediated ¹¹C-cyanation of various (hetero)aromatic bromides was performed to exhibit the tolerance of most functional groups and to provide ¹¹C-cyanated products in good to moderate radiochemical yields.

Selective deuterium installation into small molecules is becoming increasingly desirable not only for the elucidation of mechanistic pathways and studying biological processes but also because of deuterium's ability to favorably adjust the pharmacokinetic parameters of bioactive molecules. Fused bicyclic moieties, especially those containing heteroatoms, are prevalent in drug discovery and pharmaceuticals. Herein, we report a copper-catalyzed transfer hydrodeuteration of cyclic and heterocyclic alkenes, which enables the synthesis of chromans, quinolinones, and tetrahydronaphthalenes that are precisely deuterated at the benzylic position. We also demonstrate the ability to place one deuterium atom at the homobenzylic site of these scaffolds with high regioselectivity by swapping transfer reagents for their isotopic analogs. Furthermore, examples of chemoselective transfer hydrogenation and transfer deuteration are disclosed, allowing for the simultaneous incorporation of two vicinal hydrogen or deuterium atoms into a double bond.

Angiotensin II type 1 receptors (AT₁R) blocker losartan is used in patients with renal and cardiovascular diseases. [¹⁸F]fluoropyridine-losartan has shown favorable binding profile for quantitative renal PET imaging of AT₁R with selective binding in rats and pigs, low interference of radiometabolites and appropriate dosimetry for clinical translation. A new approach was developed to produce [¹⁸F]fluoropyridine-losartan in very high molar activity. Automated radiosynthesis was performed in a three-step, two-pot, and two-HPLC-purification procedure within 2 h. Pure [¹⁸F]FPyKYNE was obtained by radiofluorination of NO₂PyKYNE and silica-gel-HPLC purification (40 ± 9%), preventing the formation of nitropyridine-losartan in the second step. Conjugation with trityl-losartan azide via click chemistry, followed by acid hydrolysis, C18-HPLC purification and reformulation provided [¹⁸F]fluoropyridine-losartan in 11 ± 2% (decay-corrected from [¹⁸F]fluoride, EOB). Using tris[(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methyl]-amine (THPTA) as a Cu(I)-stabilizing agent for coupling [¹⁸F]FPyKYNE to the unprotected losartan azide afforded [¹⁸F]fluoropyridine-losartan in similar yields (11 ± 3%, decay-corrected from [¹⁸F]fluoride, EOB). Reverse-phase HPLC was optimized by reducing the pH of the mobile phase to achieve complete purification and high molar activities (467 ± 60 GBq/μmol). The use of radioprotectants prevented tracer radiolysis for 10 h (RCP > 99%). The product passed the quality control testing. This reproducible automated radiosynthesis process will allow in vivo PET imaging of AT₁R expression in several diseases.

Since first becoming commercially available in 2018, the PET radiopharmaceutical [¹⁸F]PSMA-1007 has been used widely for the diagnosis and staging of prostate cancer. A pharmacopoeia monograph first became available in 2021, prescribing a radiochemical purity specification of >91%, based on analytical results from both TLC (for [¹⁸F]fluoride impurity alone) and HPLC (for all other ¹⁸F-impurities). Though this monograph has provided clarity for the quality control testing of [¹⁸F]PSMA-1007, it prescribes a HPLC method using phosphate buffer mobile phase that may present a risk of precipitation of phosphate salts in the HPLC system. The method also requires specialised hardware not immediately available to all laboratories. This work describes the development of a simple, rapid reversed-phase HPLC method utilising 0.1 M ammonium formate mobile phase for the accurate assessment of both [¹⁸F]fluoride impurity and overall radiochemical purity in a single test. This method is especially useful for assessment of product stability over time. A more accurate TLC method for [¹⁸F]fluoride impurity is also described.

A radiochemical synthesis of [¹⁸F]DK222, a peptide binder of programmed death ligand 1 protein, suitable for human PET studies is described, and results from validation productions are presented. The high specific activity radiotracer product is prepared as a sterile, apyrogenic solution that conforms to current Good Manufacturing Practice (cGMP) requirements. In addition, the production is extended to use a commercial synthesizer platform (General Electric FASTlab 2).

We report here the detailed radiosynthesis of [¹⁸F]mG4P027, a metabotropic glutamate receptor 4 (mGluR4) PET radiotracer, which showed superior properties to the currently reported mGluR4 radiotracers. The radiosynthesis in the automated system has been challenging, therefore we disclose here the major limiting factors for the synthesis via step-by-step examination. And we hope this thorough study will help its automation for human use in the future.

Pretargeting imaging has gained a lot of prominence, due to its excellent bioorthogonality and improved imaging contrast compared to conventional imaging. A new iodo tetrazine (Tz) derivative has been synthesized and further developed into the corresponding iodine-125 (¹²⁵I) analog (12), via the trimethylstannane precursor. Radiolabeling with either N-chlorosuccinimide or chloramine-T, in either MeCN or MeOH proceeded with a radiochemical conversion (RCC) of >80%. Subsequent deprotection only proved successful, among the tested conditions, when the radiolabeled Tz was stirred in 6-M HCl_(aq.) at 60°C for 2.5 h. To the best of our knowledge, this is the first H-tetrazine labeled with iodine. In vivo investigations on the pretargeting ability of 12 are currently under way.

This paper describes the deuterium-labelling of alkylnitroaromatics by base-catalysed exchange with deuterium oxide. As the alkyl protons alpha to the aromatic ring are the most acidic sites in the molecule, regioselective hydrogen isotope exchange at this benzylic location leads to a regiospecifically deuterated product. The exchange labelling takes place in good yields and with high atom% abundance in the presence of an appropriate nitrogen base. Alkylated 2,4-dinitrobenzenes deuterate at room temperature under catalysis by triethylamine, whilst alkylated 2-nitro- or 4-nitrobenzenes and related mono-nitroaromatics require higher temperatures and catalysis by 1,5-diazobicyclo[4.3.0]non-5-ene (DBN). The labelling reactions require an inert gas atmosphere, but otherwise are simple and high yielding with no obvious byproducts. Those compounds in which the benzylic protons are in an ortho-orientation with respect to the nitro group label somewhat more slowly than the analogues where there is a para relationship. In addition, higher alkyl homologues undergo benzylic deuteration at slower rates than methyl.

Ibrutinib is an oral medication for the treatment of B cell malignancies. During its clinical development, a stable isotopologue of ibrutinib was required for the assessment of the drug's absolute oral bioavailability via intravenous microdosing. The following work describes a 10-step, gram-scale production of carbon-13 labeled ibrutinib from [¹³C₆]phenol (¹³C₆, 99%) in 31% overall yield with >99% chemical purity and >99% enantiomeric excess (ee), suitable for intravenous microdosing in humans.