Monoamine oxidase B (MAO-B) is highly expressed in reactive astrocytes and is implicated in multiple neurodegenerative and neuropsychiatric conditions, making it an important PET imaging target. Building on the promising PET imaging properties of (S)-(2-methylpyrid-5-yl)-6-[(3-18F-fluoro-2-hydroxy)propoxy]quinoline ((S)-[18F]SMBT-1), we developed a carbon-11-labeled analog, (S)-(2-11C-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ((S)-[11C]SMBT-1). The short half-life of carbon-11 (t1/2 = 20.7 min) enables same-day, repeat scans and pharmacological challenge studies within the same subject. An efficient radiosynthesis of (S)-[11C]SMBT-1 was developed via palladium-mediated Stille cross-coupling followed by acid deprotection. The radiosynthesis was completed within 28.4 ± 0.9 min from end of bombardment (EOB) (n = 3), providing (S)-[11C]SMBT-1 in 11.9% ± 2.7% radiochemical yield (decay-corrected) with final product activity of 1.76 ± 0.28 GBq (47.4 ± 7.5 mCi) and molar activity of 58.8 ± 8.0 GBq/μmol (1.59 ± 0.22 Ci/μmol) at end of synthesis (EOS), high radiochemical purity (> 99%) and enantiomeric excess (> 99%). The developed radiosynthetic method provides reliable access to (S)-[11C]SMBT-1, and in vivo evaluation studies are currently underway to further assess its potential for future clinical MAO-B PET imaging applications.
Natural pyrethrins and their analogues, synthetic pyrethroids, are widely used insecticides due to rapid action and broad efficacy. For tracer studies to comprehensively assess their safety, carbon-14 (14C)-labeled compounds are required. However, the conventional batch synthesis of 14C-labeled chrysanthemic acid-a key precursor for labeled pyrethroids-poses several challenges, including the handling of explosive and volatile intermediates, the management of safety concerns, and radioactive contamination risk. To address these issues, we have developed the first multistep continuous flow synthesis of 14C-labeled cis/trans-chrysanthemic acid. Our approach utilizes a series of sealed devices to perform diazotization, rhodium (Rh)-catalyzed cyclopropanation, hydrolysis, and continuous extractive workup without isolating hazardous intermediates. This setup enables safe, efficient, and scalable production, as the continuous flow system allows direct transfer between reaction steps and the rapid adjustment of scale by modulating feed rates. The newly developed flow synthesis of 14C-labeled cis/trans-chrysanthemic acid demonstrated significantly reduced safety concerns and the risk of radioactive contamination and improved operational efficiency compared with the conventional batch method.
Acetylpromazine, 1-{10-[3-(dimethylamino)propyl]-10H-phenothiazin-2-yl}ethenone, C19H22N2OS, 326.46 g·mol-1 is a phenothiazine derivative at one time used in human medicine as an antipsychotic medication but now predominantly used in veterinary medicine as a sedative/tranquilizer and referred to as acepromazine. In performance horses its use is regulated by using a 10 ng/mL threshold for the major urinary metabolite 2-(1-hydroxyethyl) promazine-sulfoxide (HEPS) in equine urine. To enable accurate quantitation of HEPS in equine urine we have synthesized and purified hydroxyethylpromazine sulfoxide-d4 (HEPS-d4) to be used as a stable isotopically labeled internal standard. Although labeled HEPS is commercially available (CAS 1346605-30-8), to the best of our knowledge there is no published synthetic procedure in the scientific literature. Here we demonstrate a viable synthetic procedure consisting of four major steps: (i) freebasing the Acepromazine maleate salt, (ii) H-D exchange of Acepromazine at room temperature, (iii) reduction of the ketone with NaBD4, and (iv) oxidation of the thioether via hydrogen peroxide and acetic acid. This deuterated internal standard will allow for precise LC/MS quantitation of HEPS at regulatory threshold concentrations, enabling accurate detection and quantitation of picogram/mL concentrations in equine urine samples, thereby supporting regulatory compliance for equine medication control programs.
The synthesis of deuterated compounds is a major stumbling block in the field of neutron total scattering on disordered materials. This is due to the requirement for large quantities of pure sample with high deuterium content across all positions. Typical deuterations in literature focus on site-specific deuterations typically on milligram scales. Here, we successfully synthesised paracetamol-d9, as well as its related isotopologues, on a multigram scale. We proceeded through an acid-catalysed deuteration of 4-aminophenol under microwave irradiation. We were able to efficiently purify the unstable intermediate, 4-aminophenol-d4 by sublimation, which meant we could avoid the formation of strongly coloured impurities that could not be removed from the final product otherwise. The pure intermediate then underwent acetylation with a 75% yield. More than 10 g of the final perdeuterated product was synthesised with an average deuterium incorporation of > 93% and no less than 78% at any individual position.
ABSTRACT The translocator protein (TSPO) is a mitochondrial biomarker overexpressed in activated immune cells and various tumors that is an attractive target for positron emission tomography (PET) imaging of inflammation and the tumor microenvironment. We designed and evaluated the novel TSPO‐targeted PET tracer, 64 Cu‐purine ([ 64 Cu] 5 ), constructed from a purine scaffold conjugated to a NOTA chelator. Molecular docking analysis indicated that the DOTA analog exhibited slightly higher TSPO binding affinity than did the NOTA derivative; however, the NOTA chelator was selected for 64 Cu labeling due to its superior radiochemical yield and stability. [ 64 Cu] 5 demonstrated high radiochemical purity, excellent in vitro and in vivo stability, and moderate lipophilicity, which minimized nonspecific uptake. In vitro, [ 64 Cu] 5 showed significantly higher uptake in inflammatory macrophages than in tumor cells. In vivo PET imaging and biodistribution studies revealed preferential accumulation in inflamed and tumor tissues, with reduced uptake following PK11195 administration. Autoradiography and immunohistochemistry confirmed tracer accumulation in both inflamed and tumor tissues, reflecting the presence of inflammation within the tumor microenvironment. Overall, these findings suggest that [ 64 Cu] 5 is a promising TSPO‐targeting PET radiotracer for imaging inflammation‐associated processes in tumors.
The aim of this study was to further understand the tau imaging agent, flortaucipir (T807), by making small modifications and assess its effect on tau protein binding in Alzheimer's disease ( AD ). Thus, the fluoropyridyl group in T807 was replaced with an iodine atom. We report here the development and preliminary evaluation of [ 125 I]7‐iodo‐5H‐pyrido[4,3‐B]indole ([ 125 I]CTAU) in postmortem AD brain slices. Using molecular docking, binding energies of CTAU indicated weaker tau binding compared with T807. In vitro tau binding assays in AD brain slices measured IC 50 of CTAU and T807 as 44 × 10 −9 M and 3.8 × 10 −9 M, respectively. [ 125 I]CTAU was synthesized in high radiochemical purity and molar activity (90 TBq/mmole). Binding of [ 125 I]CTAU in the AD grey matter (GM) was observed, with lower nonspecific binding in the white matter (GM/WM = 2.3). Tau binding drugs (T807 and MK‐6240, 10 μM) were both able to displace ~90% of bound [ 125 I]CTAU in AD brain slices. Clorgyline (10 μM), a monoamine oxidase A inhibitor, decreased the binding of [ 125 I]CTAU to 72% of total. In AD brain slices, [ 125 I]CTAU exhibited a similar binding profile with the tau imaging agent [ 125 I]IPPI. Although [ 125 I]CTAU appears promising in vitro, any off‐target issues need to be further studied to determine its use in AD ‐related dementias (ADRD).
Carbon‐14 labeling is fundamentally important for supporting the development of new agrochemicals and pharmaceuticals. Given its critical importance, continued innovation in technologies and methodologies for radiolabeling should be strongly encouraged to better support the radiochemistry community. However, a persistent gap often exists between technological breakthroughs and their broad adoption by the scientific community. To help bridge this gap, we have developed a Practitioner Protocol detailing a recent method from our laboratory. This protocol describes how to produce 14 C‐labeled carbon monoxide ([ 14 C]CO) directly from the universal precursor, [ 14 C]carbon dioxide ([ 14 C]CO 2 ). We hope this protocol will facilitate the adoption and implementation of this technology in other radiochemistry laboratories, thereby enhancing radiolabeling capabilities across the field.
