Journal of labelled compounds & radiopharmaceuticals最新文献

Bupivacaine is a local anesthetic widely used in equine and human medicine. Use of bupivacaine in performance horses is regulated because its ability to block pain means that it can be misused for advantage in performance horses. In racing regulation, bupivacaine is classified by the Association of Racing Commissioners International (ARCI) as a Class 2 Penalty Class A Foreign substance, the detection of which can lead to significant penalties. In horses, bupivacaine is metabolized by Phase-I hydroxylation to yield 3-hydroxybupivacaine, which is then glucuronidated to yield the Phase-II metabolite bupivacaine-3-hydroxyglucuronide, which is excreted at relatively high concentrations in equine urine. Standard regulatory procedure during urinalysis is to perform an enzymatic hydrolysis, thereby enabling subsequent detection of 3-hydroxybupivacaine, the primary analyte used for bupivacaine regulation in urine samples from competition horses. We now report on the synthesis of 3-hydroxybupivacaine and deuterated 3-hydroxybupivacaine from piperidine-2-carboxylic acid in six successive steps with moderate yield. The compounds were characterized by ¹H and ¹³C NMR and their purity ascertained by HPLC-MS. The deuterated bupivacaine and 3-hydroxybupivacaine were further confirmed by HRMS. The synthesis of these compounds provides certified reference standards and stable isotope-labeled internal standards for drug testing in competitive equine sports including horse racing.

Polyethylene terephthalate (PET) is one of the most extensively used plastics in daily life. Due to its prevalent use, it is ubiquitous in the environment and a significant contributor to plastic pollution. Continuous exposure to photochemical, thermal, biological, and mechanical processes makes PET susceptible to slow degradation and the production of microsized and/or nanosized particles known as PET microplastic/nanoplastic (MP/NP). MP/NP are widely detected in the environment, including in drinking water and human food; consequently, knowledge gaps on the impacts of MP/NP in human food sources have gained global attention. A large knowledge gap is the bioaccumulation and fate of PET MP/NP in food animals. The application of carbon-14 labeled PET NP in food animals would provide a relatively straightforward approach to understanding the degree of PET absorption and its tissue distribution after absorption. Here, a simple, fast, and efficient synthetic method is described to produce [¹⁴C]-PET NP. The method comprises the polycondensation of terephthaloyl chloride and readily accessible [¹⁴C]-ethylene glycol followed by nanoprecipitation. The synthesized [¹⁴C]-PET and [¹⁴C]-PET NP were characterized by nuclear magnetic resonance spectroscopy (NMR), Fourier transform infrared spectroscopy (FTIR), dynamic light scattering spectroscopy, thermogravimetric analyzer (TGA), and UV-Vis spectroscopy.

This study reports the automated radiosynthesis and evaluation of [¹⁸F]FPMBBG, a radiopharmaceutical designed to target the norepinephrine transporter (NET). A newly developed fully protected benzylguanidine precursor, which prevents interference from non-protected benzylguanidine part during the nucleophilic process, has enabled a one-pot two-step fully automated cassette-based synthesis of [¹⁸F]FPMBBG. This advancement enhances the feasibility of the synthesis, ensures reproducibility, and allows for the production of substantial quantities of the radiotracer, paving the way for future clinical applications. [¹⁸F]FPMBBG was prepared in radiochemical yield of ~ 23% (n = 6, decay-corrected) within 70 min, with a radiochemical purity exceeding 98%, and molar activity of > 2 GBq/μmol. In studies using miniature Bama pigs, [¹⁸F]FPMBBG showed favorable distribution, providing high-contrast cardiac images at an early stage. Moreover, desipramine inhibition studies confirmed the high NET specificity of [¹⁸F]FPMBBG. The efficient automated synthesis, robust heart uptake, and minimal background signal highlight [¹⁸F]FPMBBG as a promising PET tracer for assessing cardiac sympathetic neuronal function.

Colony-stimulating factor 1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase, is significantly expressed in mononuclear phagocytes and in the central nervous system. It has been identified as a potential drug and imaging target in numerous inflammatory, cancerous, and neurodegenerative diseases. Despite several attempts, no validated CSF1R PET tracer is currently available. Herein, we report the design and synthesis of a ¹⁸F-radiolabeled pyrrolo[2,3-d]pyrimidine molecule based on previously developed potent and selective CSF1R inhibitors. Initially, a nonlabeled fluorinated compound was synthesized using conventional and microwave methods, and it exhibited potent CSF1R inhibitory activity (IC₅₀ = 6 nM). A tosylate precursor was then synthesized for subsequent radiofluorination. The ¹⁸F-radiolabeled compound was produced using K[¹⁸F]F Kryptofix 222 (K_2.2.2)-carbonate in acetonitrile (10% DMF). The optimal labeling conditions, with a tosylate leaving group at 100°C for 5 min, resulted in the production of the ¹⁸F-radiolabeled pyrrolo[2,3-d]pyrimidine CSF1R inhibitor with high purity and with a molar activity of the final product of 57 GBq/μmol. The synthesized inhibitor might open new possibilities for in vivo imaging in neuroinflammation and related disorders, and future studies will evaluate its performance as a PET tracer.

Poly (ADP-ribose) polymerase 1 (PARP1) plays critical roles in DNA repair, chromatin regulation, and cellular equilibrium, positioning it as a pivotal target for therapeutic interventions in cancer and central nervous system (CNS) disorders. PARP1 responds to oxidative stress and DNA damage through PARylation, influencing energy depletion, survival, inflammation, and genomic regulation in many biological scenarios. PARP inhibitors (PARPis) have demonstrated efficacy against cancers harboring defective homologous recombination repair pathways, notably those linked to BRCA mutations. PARP1-targeted PET imaging enables patient stratification, treatment assessment, and PARPi pharmacodynamic evaluation in cancers and other pathophysiological conditions. Importantly, PARP1-targeted theranostics have emerged for both diagnostic imaging and therapeutic applications in multiple types of cancers, representing a pivotal advancement in personalized oncology. However, its application in brain tumors is limited by the heterogeneous integrity of the blood brain barrier (BBB) and the blood-tumor barrier. Thus, the development of BBB-penetrant PARP1 tracers remains an unmet need for imaging brain cancers. This review summarizes the current landscape of radiopharmaceuticals and radioligands targeting PARP1, detailing their pharmacological characteristics and potential clinical uses. Furthermore, this review discusses PARP1 tracers that can cross the BBB, underscoring their potential applications in neurooncology and other neurological disorders.

Biologists have significantly improved various techniques for confirming the physiological and pharmacological activity of new proteins produced by recombinant DNA technology, such as Western blotting, ELISA, and flow cytometry. Although these methods are costly and comparatively low in efficiency, our study focuses on developing a real-time approach to investigate the physiological activity of our new recombinant human insulin (rh-Insulin), which is expressed in Escherichia coli. An in vivo biodistribution study of radioiodinated rh-Insulin (¹²⁵I-rh-Insulin) was conducted in diabetic-induced mice, exploiting the capability of tyrosine residues in protein molecules to undergo electrophilic substitution of hydrogen atoms with traceable ¹²⁵I atoms. We studied many factors to optimize the conditions for the iodination reaction, including the amount of substrate, the amount of chloramine-T, pH, temperature, and reaction time. A high radiochemical yield of 99.01 ± 0.2% was achieved. The in vivo step involved the administration of ¹²⁵I-rh-Insulin intravenously (I.V.) in previously induced diabetic mice to study the pharmacokinetics of the new insulin analog. Results show a homogeneous distribution of insulin molecules throughout the body organs, correlating with organ mass, size, and functionality, with no accumulation in distinct organs. The clearance of insulin from the body occurs via both renal and hepatic routes due to the aqueous nature of insulin. Additionally, a parallel experiment was conducted on diabetic mice using only rh-Insulin, resulting in a significant reduction in glucose levels in the mice's blood, thereby exploring the physiological activity of insulin and confirming the ability of our new construct to lower blood glucose levels in diabetic mice. Consequently, this method appears to be much more rapid and effective for the evaluation of biological molecules in vivo using radioactive tracing techniques.

(R)-2-(4-(5-Chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (BI 1015550, 1) is a potent and selective inhibitor of phosphodiesterase type 4 (PDE4) being developed for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). We report the synthesis of this drug candidate labelled with carbon 14 and deuterium. The carbon 14 synthesis was completed in three radioactive steps in 27% overall yield, with a specific activity of 52 mCi/mmol (1.92 GBq/mmol), radiochemical purity, and enantiomeric excess higher than 99%. The deuterium labelled compound was prepared in seven steps in 67% overall yield and with isotopic enrichment, chemical purity, and enantiomeric excess higher than 99%.

Deuterium-labeled pyocyanin was prepared from deuterium-labeled phenazine methosulfate in gram scale by a simplified flow photosynthesis in water. The main product was the protonated red form of pyocyanin-d₃ (Pyo-d₃-H⁺) in 85 % yield. Quantum chemical calculations of NMR support that nitrogen-10 is protonated. The by-products of the photolysis and the stability of the photolysis mixture were carefully characterized by LC-MS and NMR. Four by-products were identified: An isomer of pyocyanin-d₃ (9%), 8-hydroxypyocyanin-d₃ (4%), 1-hydroxyphenazine (0.4%), and phenazine (1%). The Pyo-d₃-H⁺ product was stable in the photolysis solution after storage at 8°C for 2.5 years. Pure blue pyocyanin-d₃ powder was isolated from the red photolysis solution by the Surrey method in 94 % yield. The addition of the red photolysis solution of Pyo-d₃-H⁺ (100 μM) and commercial pyocyanin (100 μM) to Pseudomonas aeruginosa cultures showed the same growth curves demonstrating that the minor impurities in the photolysis solution do not affect the growth behavior of the bacteria. The protonated deuterium-labeled pyocyanin may be used directly in biological experiments, which make the methodology extremely simple and useful for biologists.