Journal of labelled compounds & radiopharmaceuticals最新文献

The vascular endothelial growth factor A (VEGF-A)/VEGF receptor 2 (VEGFR-2) signaling pathway is pivotal in regulating angiogenesis. We have synthesized a linear peptide-based VEGFR-2–targeted positron emission tomography (PET) tracer, but its target affinity and in vivo stability need further improvement. In this study, we developed two novel ⁶⁴Cu-labeled VEGFR-2–targeted PET dimer tracer [⁶⁴Cu]VEGF₂₂₁₅ and [⁶⁴Cu]VEGF₂₂₁₆ modified with a pegylated linear and branched linker, respectively, to optimize its pharmacokinetic properties and conducted a comprehensive preclinical assessment. Both tracers exhibited a radiochemical yield of over 95% and showed a high affinity for VEGFR-2 in U87MG cells. PET/CT imaging experiments indicated that [⁶⁴Cu]VEGF₂₂₁₅ exhibited a time-dependent accumulation in the U87MG tumor, with a maximum uptake of 4.95 ± 1.26 %ID/g at 24 h post-injection. In comparison, [⁶⁴Cu]VEGF₂₂₁₆ showed a consistently lower tumor uptake, peaking at only 3.07 ± 0.35 %ID/g. Blocking and biodistribution experiments further confirmed the specificity of [⁶⁴Cu]VEGF₂₂₁₅ for VEGFR-2. The favorable properties of [⁶⁴Cu]VEGF₂₂₁₅, including efficient synthesis, high tumor uptake, and rapid clearance from most normal organs, suggest it is a promising PET tracer for VEGFR-2-positive tumors.

[¹⁸F]Florbetazine injection, a radiotracer that could target Aβ plaques and achieve diagnosis of Alzheimer's disease (AD), is a novel positron emission tomography (PET) imaging agent currently in the investigational new drug (IND) application stage. The active ingredient of [¹⁸F]Florbetazine injection, [¹⁸F]Florbetazine, is a diaryl-azine derivative. Chemical and radiochemical purity is critical quality attributes (CQAs) for [¹⁸F]Florbetazine injection, and thus, we have developed and validated a relevant HPLC method. This study describes the specificity, linearity, accuracy, repeatability, and limit of quantification (LOQ) of the HPLC method. The stability of three sample batches was investigated using the established method. The validation results demonstrated the accuracy, precision, and sensitivity of the method, making it suitable for implementation as part of the quality control (QC) process for [¹⁸F]Florbetazine injection. The stability of three sample batches revealed a decrease in concentration and radiochemical purity over 10 h. However, all samples maintained a radiochemical purity of over 90% after 10 h. The results provided a foundation for establishing quality standards for [¹⁸F]Florbetazine injection. The same methodology employed in this study could be applied and modified for QC protocols of other ¹⁸F-labeled radiopharmaceuticals.

Most of the reported small molecule-based fibroblast activation protein (FAP)-targeted radioligands are derived from UAMC1110 and contain a 4-difluoro-2-cyanopyrrolidine moiety. In this study, we investigated the effect of replacing the 4-difluoro-2-cyanopyrrolidine moiety of [⁶⁸Ga]Ga-FAPI-04 with 2-azabicyclo[3.1.0]hexane-3-carbonitrile on the in vitro/vivo FAP-targeting capability. The newly derived ⁶⁸Ga-labeled FAP-targeted tracer, [⁶⁸Ga]Ga-JC02076, was obtained in 43.5 ± 10.4% decay-corrected radiochemical yield within 33.5 ± 5.8 min (n = 4). The radiochemical purity and molar activity were 97.2 ± 3.4% and 411.6 ± 232.5 GBq/μmol, respectively. Ga-JC02076 showed good binding affinity for FAP (IC₅₀ = 29.7 ± 3.5 nM). Most importantly, [⁶⁸Ga]Ga-JC02076 enabled clear visualization of HEK293T:hFAP tumor xenografts in PET images and had good tumor uptake (7.17 ± 2.19 %ID/g) and excellent tumor-to-bone (17.3 ± 6.99) and tumor-to-muscle (32.3 ± 12.5) uptake ratios at 1 h post-injection. Our data suggest that N-(4-quinolinoyl)-Gly-(2-azabicyclo[3.1.0]hexane-3-carbonitrile) is a promising pharmacophore for the design of FAP-targeted tracers.

Cyclin-dependent kinase 19 (CDK19) is a potential target for the diagnosis and treatment of prostate cancer. We have previously studied a series of CDK19-targeted PET tracers, but in-depth drug optimization is needed to improve the physiochemical properties of such large and polar tracers. The albumin strategy has received widespread attention in recent years, and we synthesized ⁶⁸Ga-IRM-14a and ⁶⁸Ga-IRM-14b based on the strategy. After in vivo imaging studies in mice, we found that introducing albumin moiety will significantly change the physicochemical properties of existing large polarity tracers, thereby increasing tissue uptake and retention, which is beneficial for future treatment. In short, the albumin strategy will be an important strategy in the field of radiopharmaceutical optimization.

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.

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.