Journal of labelled compounds & radiopharmaceuticals最新文献

[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.

An in-loop ¹¹C-carbonylation process for the radiosynthesis of ¹¹C-carboxylic acids and esters from halide precursors has been developed. The reaction proceeds at room temperature under mild conditions and enables ¹¹C-carbonylation of both electron deficient and electron rich (hetero)aromatic halides to provide ¹¹C-carboxylic acids and esters in good to excellent radiochemical yields, high radiochemical purity, and excellent molar activity. The process has been fully automated using commercial radiochemistry synthesis modules, and application to clinical production is demonstrated via validated cGMP radiosyntheses of [¹¹C]bexarotene and [¹¹C]acetoacetic acid.

Created literally at the dawn of time, deuterium has been extremely valuable in so many chemistry roles. The subject of this review focuses on one deuterium application in particular: its enhancement of luminescence in many substances. After providing general overviews of both deuterium and luminescence, the early exploration of deuterium's effect on luminescence is described, followed by a number of specific topics. These sections include a discussion of deuterium-influenced luminescence for dyes, proteins, singlet oxygen, and the lanthanide elements, as well as anomalous inverse deuterium luminescence effects. Future directions for this important research topic are also proposed, as well as a summary conclusion.

Halogenated, labeled with deuterium, tritium or doubly labeled with deuterium and tritium in the 3S position of the side chain isotopomers of L-phenylalanine and phenylpyruvic acid were synthesized. Isotopomers of halogenated L-phenylalanine were obtained by addition of ammonia from isotopically enriched buffer solution to the halogenated derivative of (E)-cinnamic acid catalyzed by phenylalanine ammonia lyase. Isotopomers of halogenated phenylpyruvic acid were obtained enzymatically by conversion of the appropriate isotopomer of halogenated L-phenylalanine in the presence of phenylalanine dehydrogenase. As a source of deuterium was used deuterated water, as a source of tritium was used a solution of highly diluted tritiated water. The labeling takes place in good yields and with high deuterium atom% abundance.

(R)-2-(4-(Benzo[d]oxazol-2-yl)piperazin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (1) and (R)-2-(4-(4-chlorophenoxy)piperidin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (2) are two potent and selective inhibitors of phosphodiesterase type 4 (PDE4). In this manuscript, we report the detailed synthesis of these two compounds labeled with carbon 14 and with stable isotopes. The core (R)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide is common in both inhibitors. In the radioactive synthesis, the carbon 14 atom was introduced in the benzoxazole moiety using [¹⁴C]carbon disulfide to obtain [¹⁴C]-1 in five steps at a 55% overall yield. [¹⁴C]Urea was used to incorporate the carbon 14 atom in two steps in the dihydrothieno[3,2-d]pyrimidine intermediate, which was then transformed in four more steps to [¹⁴C]-2 at a 30% overall yield. Both compounds were isolated with specific activities higher than 54 mCi/mmol, radio- and chemical-purities higher than 99%, and with excellent enantiomeric excess. In the stable isotope synthesis, [²H₈]piperazine was used to prepare [²H₈]-1 in three steps in 72% overall yield, while [¹³C₆]phenol was used to prepare [¹³C₆]-2 in four steps in 18% overall yield.

The cover image is based on different strategies covered within this issue used for crossing the blood brain barrier.

SMS would like to acknowledge Simon Zientek (University of Cambridge) for helpful discussion about the cover image.

Positron emission tomography (PET) using O-(2-[¹⁸F]fluoroethyl)-L-tyrosine ([¹⁸F]FET) has shown great success in differentiating tumor recurrence from necrosis. In this study, we are reporting the experience of synthesis [¹⁸F]FET by varying the concentration of TET precursor in different chemistry modules. TET precursor (2–10 mg) was used for the synthesis of [¹⁸F]FET in an automated (MX Tracerlab) module (n = 6) and semiautomated (FX2N Tracerlab) module (n = 19). The quality control was performed for all the preparations. For human imaging, 220 ± 50 MBq of [¹⁸F]FET was briefly injected into the patient to acquire PET-MR images. The radiochemical purity was greater than 95% for the final product in both modules. The decay corrected average yield was 10.7 ± 4.7% (10 mg, n = 3) and 8.2 ± 2.6% (2 mg, n = 3) with automated chemistry module and 36.7 ± 7.3% (8–10 mg, n = 12), 26.4 ± 3.1% (5–7 mg, n = 4), and 35.1 ± 3.8% (2–4 mg, n = 3) with semiautomated chemistry modules. The PET imaging showed uptake at the lesion site (SUV_max = 7.5 ± 2.6) and concordance with the MR image. The [¹⁸F]FET was produced with a higher radiochemical yield with 2.0 mg of the precursor with substantial yield and is suitable for brain tumor imaging.