Journal of labelled compounds & radiopharmaceuticals最新文献

Bruton's tyrosine kinase (BTK) is a cytoplasmic enzyme that plays a crucial role in B cell development, survival, proliferation and differentiation. This enzyme is expressed in several autoimmune diseases and cancers. Therefore, shutting out this enzyme with irreversible inhibitors is one of the strategies used to treat these diseases. The drug candidate 1 is a very potent and selective BTK inhibitor. Herein, we describe the preparation of this compound labelled with deuterium and carbon-14. Deuterium labelled 1 was prepared in 10 chemical steps and in 35% overall yield with more than 98% chemical purity and more than 99% isotopic enrichment. This synthesis was followed with the radioactive one as both synthetic routes were similar. Carbon-14 labelled 1 was prepared in eight radiochemical steps in 26% overall yield and in more than 99% radio and chemical purities and with specific activity of 53.1 mCi/mmol (1.96 GBq/mmol). This isotopically labelled compound was needed for DMPK and other studies.

Dopamine transporter (DAT) is closely associated with neurodegenerative diseases such as Parkinson's disease (PD). To develop an in vivo stable radioligand targeting DAT, we synthesized a novel iodine-131-labeled tropane analog [¹³¹I]1 with deuteration on both the N-fluoropropyl and 2β-carbomethoxy positions of the tropane scaffold and then biologically compared with the previously reported analog [¹³¹I]FP-CIT-d₆ with deuteration only on the N-fluoropropyl group. The radioligand [¹³¹I]1 was obtained via a radioiodine-destannylation reaction with a radiochemical yield of ~95%, a radiochemical purity of > 99% and a molar activity of 12.72 GBq/μmol. [¹³¹I]1 exhibited a high in vitro binding affinity for DAT with an IC₅₀ value of 2.2 nM. Metabolic stability studies demonstrated that [¹³¹I]1 displayed superior in vivo stability compared with [¹³¹I]FP-CIT-d₆. Biodistribution studies revealed that [¹³¹I]1 had better DAT affinity, specificity, and a higher target-to-background ratio than [¹³¹I]FP-CIT-d₆. Ex vivo autoradiography and blocking experiments validated the selective and reversible binding of [¹³¹I]1 to DAT and superiority to [¹³¹I]FP-CIT-d₆. These preliminary results suggest that deuterated radioligand [¹³¹I]1, with enhanced in vivo stability and higher target-to-background ratio, is a promising DAT probe, warranting the development and application of ¹²³I-labeled counterpart ([¹²³I]1) for SPECT imaging in DAT-related disorders.

Animal models of Alzheimer's disease (AD) are essential for developing therapeutics and evaluating the efficacy of new drug candidates. Positron emission tomography (PET) is a useful method to monitor a major hallmark of the onset of AD, namely, the deposition of amyloid β peptide (Aβ) in the brain. [¹⁸F]FC-119S (1), a 2-pyridylbenzothiazole analog, has been applied as a radiotracer for PET visualization of Aβ plaques in an AD model, the 5xFAD mouse. Here, we present an alternative method for the automated synthesis of ¹⁸F-labeled 1 as a radiotracer for our animal PET studies. The first attempt at synthesizing ¹⁸F-labeled 1 using a mesyl precursor afforded desired product 1, although a nonfluorinated mesyl byproduct was eluted prior to 1 during purification by semipreparative high-performance liquid chromatography. An alternative synthesis using a tosyl precursor was applied to delay the elution of a nonfluorinated byproduct during chromatographic purification. As a result, ¹⁸F-labeled 1 was eluted without proximate byproducts during chromatographic purification, and routine production of ¹⁸F-labeled 1 was achieved for our AD studies using animal models.

The existence of isotopes was proposed at the dawn of the 20^th century based on compelling experimental evidence by many distinguished investigators. The subject of this review focuses on one specific application of isotopes in the evolving science of forensics. The topics covered include isotope ratio measurement and variation, forensic anthropology, wildlife trafficking, explosive investigation, illicit drugs, counterfeit medicines, food authentication, nuclear forensics and artificial intelligence (AI). Future directions and a conclusion for this important research topic are also included.

The protein carbonic anhydrase IX (CAIX) is highly expressed in clear cell renal cell carcinoma (ccRCC), and its restrictive expression in healthy tissues makes CAIX an attractive diagnostic target. The purpose of this study was to synthesize and evaluate [¹⁸F]AlF-NY104, a small-molecule CAIX-targeting PET agent in a preclinical ccRCC model. The radiolabeling parameters for [¹⁸F]AlF-NY104 have been optimized, including the solvent volume and reaction temperature. The high-purity product was synthesized by using an automated multifunctional module Mortenon M1, leading to nondecay-corrected radiochemical yields over 50% (n = 3). [¹⁸F]AlF-NY104 showed excellent tumor targeting capability and afforded high-quality microPET/CT imaging in the OS-RC-2 tumor model (15.01 ± 0.76 %ID/g [mean ± SEM]). The radiation exposure from [¹⁸F]AlF-NY104 is estimated to be 4.44 mSv for adult male and female human subjects, which is well below the FDA recommended whole-body single exposure limit of 30 mSv. Our investigation revealed that [¹⁸F]AlF-NY104 can be conveniently and efficiently radiolabeled by using an automated module. [¹⁸F]AlF-NY104 exhibited many outstanding properties, such as rapid uptake in tumor, rapid clearance through the kidney, and low uptake in most normal organs. Moreover, the high accumulation of [¹⁸F]AlF-NY104 in tumors in CAIX-positive models offers an alternative diagnostic strategy for patients with ccRCC.

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.