Journal of labelled compounds & radiopharmaceuticals最新文献

The α4β2 nicotinic acetylcholine receptor (nAChR) ligand 2-[¹⁸F]fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine ([¹⁸F]nifene) has been synthesized in 10% decay-corrected radiochemical yield using the IBA Synthera® platform (IBA Cyclotron Solutions, Louvain-la-Neuve, Belgium) with an integrated fluidic processor (IFP). Boc-nitronifene served as the precursor, and 20% trifluoroacetic acid (TFA) was used to deprotect the Boc-group after radiolabeling. By omitting the solvent extraction step after radiolabeling, the process was simplified to a single step with no manual intervention. [¹⁸F]Nifene was obtained in decay-corrected radiochemical yields of 10 ± 2% (n = 20) and radiochemical purity >99%. Typical specific radioactivities of 2700–4865 mCi/μmole (100–180 GBq/μmol) were measured at the end of synthesis; total synthesis times were about 1 h 40 min.

Nanobodies (Nbs) hold significant potential in molecular imaging due to their unique characteristics. However, there are challenges to overcome when it comes to brain imaging. To address these obstacles, collaborative efforts and interdisciplinary research are needed. This article aims to raise awareness and encourage collaboration among researchers from various fields to find solutions for effective brain imaging using Nbs. By fostering cooperation and knowledge sharing, we can make progress in overcoming the existing limitations and pave the way for improved molecular imaging techniques in the future.

The tyrosine kinase MET (hepatocyte growth factor receptor) is activated or mutated in a wide range of cancers and is often correlated with a poor prognosis. Precision medicine with positron emission tomography (PET) can potentially aid in the assessment of tumor biochemistry and heterogeneity, which can prompt the selection of the most effective therapeutic regimes. The selective MET inhibitor PF04217903 (1) formed the basis for a bioisosteric replacement, leading to the deoxyfluorinated analog [¹⁸F]2. [¹⁸F]2 could be synthesized with a “hydrous fluoroethylation” protocol in 6.3 ± 2.6% radiochemical yield and a molar activity of >50 GBq/μmol. In vitro autoradiography indicated that [¹⁸F]2 selectively binds to MET in PC3 tumor tissue, and in vivo biodistribution in mice showed predominantly a hepatobiliary excretion along with a low retention of radiotracer in other organs.

We, herein, report the synthesis of ¹³C₂-labeled natural products from the mugineic acid and avenic acid family. These phytosiderophores (“plant iron carriers”) are built up from non-proteinogenic amino acids and play a key role in micronutrient uptake in gramineous plants. In this work, two central building blocks are prepared from labeled starting materials (¹³C₂-bromoacetic acid, ¹³C₂-glycine) and further employed in our recently reported divergent, branched synthetic strategy delivering eight isotopically labeled phytosiderophores. The required labeled building blocks (¹³C₂-l-allylglycine and a related hydroxylated derivative) were prepared via enantioselective phase-transfer catalysis and enantio- and diastereoselective aldol condensation with a chiral auxiliary, respectively, both potentially valuable themselves for other synthetic routes toward labeled (natural) products.

Nucleophilic copper-mediated radioiodination (CMRI) of organoboronic precursors with radioiodides is a promising method of radioiodination. The previously reported CMRI has demonstrated its great potential and scope of labeling for the radiosynthesis of radioiodine-labeled compounds. However, the reported protocols (using a small amount/volume of radioactivity) are practically not reproducible in large-scale CMRI, in which the radioactivity was usually provided in a bulk alkaline solution. A large amount of water and a strong base are incompatible with CMRI. To overcome these issues in large-scale CMRI, we have developed a simple protocol for large-scale CMRI. The bulk water was removed under a flow of inert gas at 110°C, and the strong base (i.e., NaOH) was neutralized with an acid, pyridinium p-toluenesulfonate or p-toluenesulfonic acid. In the model reactions of [¹²³I]KX-1, a PARP-1 radioligand for Auger radiotherapy, radiochemical conversions were significantly improved after neutralization of the base, and the addition of additional acids was tolerated and favorable for the reactions. Using this protocol, [¹²³I]KX-1 was radiosynthesized from 20 mCi (0.74 GBq) of [¹²³I]iodide in high radiochemical yields, high radiochemical purity, and high molar activity. This protocol should be applicable to the radiosynthesis of other compounds with radioiodine via CMRI.

Stable isotope labeled Iclepertin (BI 425809, 1) and its major metabolites are needed as internal standards in bioanalytical studies. BI 425809 consists of two main building blocks, 5-methylsulfonyl-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]benzoic acid (2) and 3-[(1R,5R)-3-azabicyclo[3.1.0]hexan-5-yl]-5-(trifluoromethyl)isoxazole (3) linked to each other via an amide bond. We used fluoro[¹³C₆]benzene as the starting material in the preparation of [¹³C₆]-2. This intermediate was then employed to access carbon 13 labeled Iclepertin ([¹³C₆]-1) and other metabolites. The major metabolite BI 761036 (6), which resulted from cytochrome P450 oxidation and amide hydrolysis of BI 425809, was prepared labeled with carbon 13 and nitrogen 15 via two synthetic routes. In the first route, diethyl [¹³C₃]malonate, [¹³C]methyl iodide, and hydroxyl[¹⁵N]amine were used to provide [¹³C₄,¹⁵N]-BI 761036 ([¹³C₄,¹⁵N]-6a) in 13 steps in 6% overall yield, whereas in the second route, [¹³C₃]propargyl alcohol, potassium [¹³C]cyanide, and [¹⁵N]ammonia were used to furnish [¹³C₄,¹⁵N]-BI 761036 ([¹³C₄,¹⁵N]-6b) in 11 steps in 1% overall yield. The detailed stable isotope synthesis of 1 and its major metabolites is described.

Evobrutinib is a second-generation, highly selective, irreversible Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in the autoimmune diseases arthritis and multiple sclerosis. Its development as a positron emission tomography (PET) radiotracer has potential for in vivo imaging of BTK in various disease models including several cancers, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), and lipopolysaccharide (LPS)-induced lung damage. Herein, we report the automated radiosynthesis of [¹¹C]evobrutinib using a base-aided palladium-NiXantphos-mediated ¹¹C-carbonylation reaction. [¹¹C]Evobrutinib was reliably formulated in radiochemical yields of 5.5 ± 1.5% and a molar activity of 34.5 ± 17.3 GBq/μmol (n = 12) with 99% radiochemical purity. Ex vivo autoradiography studies showed high specific binding of [¹¹C]evobrutinib in HT-29 colorectal cancer mouse xenograft tissues (51.1 ± 7.1%). However, in vivo PET/computed tomography (CT) imaging with [¹¹C]evobrutinib showed minimal visualization of HT-29 colorectal cancer xenografts and only a slight increase in radioactivity accumulation in the associated time-activity curves. In preliminary PET/CT studies, [¹¹C]evobrutinib failed to visualize either SARS-CoV-2 pseudovirus infection or LPS-induced injury in mouse models. In conclusion, [¹¹C]evobrutinib was successfully synthesized by ¹¹C-carbonylation and based on our preliminary studies does not appear to be a promising BTK-targeted PET radiotracer in the rodent disease models studied herein.

[⁶⁸Ga]Ga-PentixaFor is a frequently used radiotracer to image the CXCR4/CXCL12 axis in various malignancies, infections, and cardiovascular diseases. To answer increasing clinical needs, an automatized synthesis process ensuring efficient and reproducible production and improving operator's radioprotection is needed. [⁶⁸Ga]Ga-PentixaFor synthesis has been described on other synthesizers but not on the miniAiO. In this work, we defined automated synthesis process and an analytical method for the quality control of [⁶⁸Ga]Ga-PentixaFor. Validation batches were performed under aseptic conditions in a class A hotcell. All the quality controls required by the European Pharmacopea (Eur. Ph) were performed. The analytical methods were validated according to the International Conference Harmonization (ICH) recommendations. Validation batches were performed with a radiochemical yield of 94.8 ± 2.6%. All the quality controls were in conformity with the Eur. Ph, and the validation of the analytical method complied with the ICH. The environmental monitoring performed during the synthesis process showed that the aseptic conditions were ensured. [⁶⁸Ga]Ga-PentixaFor was successfully synthesized with the miniAiO by a fully automated process. This robust production mode and the quality control have been validated in this study allowing to increase the access of patients to this new promising radiopharmaceutical.

CRANAD-102, a selective near-infrared fluorescent tracer targeting soluble amyloid-β (Aβ) species, has recently attracted attention due to its potential to be used as a diagnostic tool for early stages of Alzheimer's disease (AD). Development of a positron emission tomography (PET) tracer based on CRANAD-102 could as such allow to noninvasively study soluble and protofibrillar species of Aβ in humans. These soluble and protofibrillar species are thought to be responsible to cause AD. Within this work, we successfully ¹¹C-labeled CRANAD-102 via a Suzuki–Miyaura reaction in a RCС of 48 ± 9%, with a RCP of >96% and a molar activity (A_m) of 25 ± 7 GBq/μmol. Future studies have to be conducted to evaluate if [¹¹C]CRANAD-102 can be used to detect soluble protofibrils in vivo and if [¹¹C]CRANAD-102 can be used to detect AD earlier as possible with current diagnostics.

The vesicular acetylcholine transporter (VAChT) in the brain is an important presynaptic cholinergic biomarker, and neuroimaging studies of VAChT may provide in vivo information about psychiatric and neurologic conditions including Alzheimer's disease that are not accessible by other methods. The ¹⁸F-labeled radiotracer, ((-)-(1-(-8-(2-[¹⁸F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-fluorophenyl)-methanone ([¹⁸F]VAT, 1), was reported as a selective and high affinity ligand for the in vivo imaging of VAChT. The synthesis of [¹⁸F]VAT has been reported in a two-step procedure with total 140 min, which includes preparation of 2-[¹⁸F]fluoroethyltosylate and alkylation of benzovesamicol (-)-5 precursor with this radiosynthon using two different automated production modules consecutively. A multiple step synthetic route was employed for the synthesis of stereospecific precursor benzovesamicol (-)-5, which is difficult to be adapted for scale-up. To make the production of this tracer more amenable for clinical imaging, we present an improved total synthesis protocol to attain [¹⁸F]VAT: (1) a tosylethoxy group being pre-installed tosylate precursor (-)-8 is synthesized to render a simple one-step radiofluorination under mild conditions; (2) The key optically active intermediate benzovesamicol (-)-5 was obtained via the regio- and enantio-enriched ring-opening amination of meso-epoxide 3 with 4-phenylpiperidine derivative 2 under catalysis of a chiral salenCo(III) catalyst 4b, which dramatically simplifies the synthetic route of the tosylate precursor (-)-8. [¹⁸F]VAT 1 was prepared within ~65 min with desired chemical and radiochemical purities, via a fully automated procedure, using a commercial PET tracer production module. The final drug product was obtained as a sterile, pyrogen-free solution that conforms United States Pharmacopeia (USP) <823> requirements.