Journal of labelled compounds & radiopharmaceuticals最新文献

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.

Positron emission tomography (PET) is a powerful tool in medicine and drug development, allowing for non-invasive imaging and quantitation of biological processes in live organisms. Targets are often probed with small molecules, but antibody-based PET is expanding because of many benefits, including ease of design of new antibodies toward targets, as well as the very strong affinities that can be expected. Application of antibodies to PET imaging of targets in the central nervous system (CNS) is a particularly nascent field, but one with tremendous potential. In this review, we discuss the growth of PET in imaging of CNS targets, present the promises and progress in antibody-based CNS PET, explore challenges faced by the field, and discuss questions that this promising approach will need to answer moving forward for imaging and perhaps even radiotherapy.

Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are promising treatments for unresectable liver tumours. Some recent studies suggested that combining TACE and TARE in one treatment course might improve treatment efficacy through synergistic cytotoxicity effects. Nonetheless, current formulations do not facilitate a combination of chemo- and radio-embolic agents in one delivery system. Therefore, this study aimed to synthesise a hybrid biodegradable microsphere loaded with both radioactive agent, samarium-153 (¹⁵³Sm) and chemotherapeutic drug, doxorubicin (Dox) for potential radio-chemoembolization of advanced liver tumours. ¹⁵²Sm and Dox-loaded polyhydroxybutyrate-co-3-hydroxyvalerate (PHBV) microspheres were prepared using water-in-oil-in-water solvent evaporation method. The microspheres were then sent for neutron activation in a neutron flux of 2 × 10¹² n/cm²/s. The physicochemical properties, radioactivity, radionuclide purity, ¹⁵³Sm retention efficiency, and Dox release profile of the Dox-¹⁵³Sm-PHBV microspheres were analysed. In addition, in vitro cytotoxicity of the formulation was tested using MTT assay on HepG2 cell line at 24 and 72 h. The mean diameter of the Dox-¹⁵³Sm-PHBV microspheres was 30.08 ± 2.79 μm. The specific radioactivity was 8.68 ± 0.17 GBq/g, or 177.69 Bq per microsphere. The ¹⁵³Sm retention efficiency was more than 99%, tested in phosphate-buffered saline (PBS) and human blood plasma over 26 days. The cumulative release of Dox from the microspheres after 41 days was 65.21 ± 1.96% and 29.96 ± 0.03% in PBS solution of pH 7.4 and pH 5.5, respectively. The Dox-¹⁵³Sm-PHBV microspheres achieved a greater in vitro cytotoxicity effect on HepG2 cells (85.73 ± 3.63%) than ¹⁵³Sm-PHBV (70.03 ± 5.61%) and Dox-PHBV (74.06 ± 0.78%) microspheres at 300 μg/mL at 72 h. In conclusion, a novel biodegradable microspheres formulation loaded with chemotherapeutic drug (Dox) and radioactive agent (¹⁵³Sm) was successfully developed in this study. The formulation fulfilled all the desired physicochemical properties of a chemo-radioembolic agent and achieved better in vitro cytotoxicity on HepG2 cells. Further investigations are needed to evaluate the biosafety, radiation dosimetry, and synergetic anticancer properties of the formulation.

Granzyme B is an attractive target as a biomarker for contributing to improve the treatment with immune checkpoint inhibitor (ICI). In this study, we designed novel ¹¹¹In-labeled granzyme B-targeting single-photon emission computed tomography (SPECT) imaging probes, [¹¹¹In]IDT and [¹¹¹In]IDAT. Nonradioactive In-labeled granzyme B-targeting compounds ([^natIn]IDT, [^natIn]IDAT) showed the affinity for recombinant mouse granzyme B. [¹¹¹In]IDT and [¹¹¹In]IDAT were obtained with moderate radiochemical yield and high stability in mouse plasma (>95%). In a biodistribution experiment using tumor-bearing mice, [¹¹¹In]IDT and [¹¹¹In]IDAT showed moderate accumulation in tumor. Ex vivo autoradiography (ARG) indicated that the accumulation of radioactivity in tumor was correlated to expression of granzyme B confirmed by the immunohistochemical staining. These results indicated that [¹¹¹In]IDT and [¹¹¹In]IDAT showed the basic properties as granzyme B-targeting SPECT probes.

Tritium-labeled compounds are generally less stable than their non-labeled counterparts. This requires storage at low temperatures, a constant workflow of quality checks, and subsequent re-purifications. As the amount of tritium-labeled material is typically purified in the μg range, repeated injections on analytical-scale ultra high-performance liquid chromatography systems can provide high-resolution re-purification results. Yet, degradants can be undesirably included in the compound isolation because the amount of decomposition can vary dramatically depending on the structure. We report a case of a sensitive molecule that could not be isolated in pure form even though the chromatographic separation was successful. In this case, the use of a small-scale two-dimensional preparative liquid chromatography approach with a direct transfer interface to a second (trapping) column resulted in a highly pure compound (>98% radiochemical purity). This approach combines high chromatographic resolution, accurate control over the re-purification process, minimal sample manipulation, and higher overall safety for the handling of radioactive samples.