Journal of labelled compounds & radiopharmaceuticals最新文献

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.

Carbon 14 labeled Iclepertin (BI 425809, 1) and its major metabolites were needed for ADME and several other studies necessary for the advancement of this drug candidate in clinical trials. Iclepertin is composed of two main chemical blocks, (R)-5-(methylsulfonyl)-2-([1,1,1-trifluoropropan-2-yl]oxy)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. In the first synthesis of carbon 14 labeled 1, 2-fluorobenzoic acid, carboxyl-¹⁴C was converted to [¹⁴C]-2 in three steps and then coupled to 3 to provide [¹⁴C]-1a in 45% overall yield. In the second synthesis, [¹⁴C]-3 was prepared in six radioactive steps and coupled to the acid 2 to furnish [¹⁴C]-1b in 20% overall yield. Both synthetic routes provided [¹⁴C]-1a and [¹⁴C]-1b with specific activities higher than 53 mCi/mmol and radiochemical, chemical, and enantiomeric purities above 98%. Two major metabolites of 1, BI 761036 and BI 758790, were also prepared labeled with carbon 14 using intermediates already available from the synthesis of [¹⁴C]-1.

The direct electrophilic deuteration of the aromatic moiety in aromatic and aralkyl amines is reported. The acid-catalyzed deuteration is facilitated by deuterated trifluoromethanesulfonic acid, [D]triflic acid, CF₃SO₃D, TfOD, which acts as both the reaction solvent and the source of the deuterium label. The mild conditions enable room temperature hydrogen/deuterium exchange for most of the para-substituted aromatic amine derivatives studied. In addition, short reaction times and a high degree of aromatic deuteration are achieved and isolation of the product is simple. The optical activity of the chiral aralkyl amines studied was preserved.