Journal of labelled compounds & radiopharmaceuticals最新文献

Poly (ADP-ribose) polymerase 1 (PARP1) plays critical roles in DNA repair, chromatin regulation, and cellular equilibrium, positioning it as a pivotal target for therapeutic interventions in cancer and central nervous system (CNS) disorders. PARP1 responds to oxidative stress and DNA damage through PARylation, influencing energy depletion, survival, inflammation, and genomic regulation in many biological scenarios. PARP inhibitors (PARPis) have demonstrated efficacy against cancers harboring defective homologous recombination repair pathways, notably those linked to BRCA mutations. PARP1-targeted PET imaging enables patient stratification, treatment assessment, and PARPi pharmacodynamic evaluation in cancers and other pathophysiological conditions. Importantly, PARP1-targeted theranostics have emerged for both diagnostic imaging and therapeutic applications in multiple types of cancers, representing a pivotal advancement in personalized oncology. However, its application in brain tumors is limited by the heterogeneous integrity of the blood brain barrier (BBB) and the blood-tumor barrier. Thus, the development of BBB-penetrant PARP1 tracers remains an unmet need for imaging brain cancers. This review summarizes the current landscape of radiopharmaceuticals and radioligands targeting PARP1, detailing their pharmacological characteristics and potential clinical uses. Furthermore, this review discusses PARP1 tracers that can cross the BBB, underscoring their potential applications in neurooncology and other neurological disorders.

(R)-2-(4-(5-Chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (BI 1015550, 1) is a potent and selective inhibitor of phosphodiesterase type 4 (PDE4) being developed for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). We report the synthesis of this drug candidate labelled with carbon 14 and deuterium. The carbon 14 synthesis was completed in three radioactive steps in 27% overall yield, with a specific activity of 52 mCi/mmol (1.92 GBq/mmol), radiochemical purity, and enantiomeric excess higher than 99%. The deuterium labelled compound was prepared in seven steps in 67% overall yield and with isotopic enrichment, chemical purity, and enantiomeric excess higher than 99%.

Deuterium-labeled pyocyanin was prepared from deuterium-labeled phenazine methosulfate in gram scale by a simplified flow photosynthesis in water. The main product was the protonated red form of pyocyanin-d₃ (Pyo-d₃-H⁺) in 85 % yield. Quantum chemical calculations of NMR support that nitrogen-10 is protonated. The by-products of the photolysis and the stability of the photolysis mixture were carefully characterized by LC-MS and NMR. Four by-products were identified: An isomer of pyocyanin-d₃ (9%), 8-hydroxypyocyanin-d₃ (4%), 1-hydroxyphenazine (0.4%), and phenazine (1%). The Pyo-d₃-H⁺ product was stable in the photolysis solution after storage at 8°C for 2.5 years. Pure blue pyocyanin-d₃ powder was isolated from the red photolysis solution by the Surrey method in 94 % yield. The addition of the red photolysis solution of Pyo-d₃-H⁺ (100 μM) and commercial pyocyanin (100 μM) to Pseudomonas aeruginosa cultures showed the same growth curves demonstrating that the minor impurities in the photolysis solution do not affect the growth behavior of the bacteria. The protonated deuterium-labeled pyocyanin may be used directly in biological experiments, which make the methodology extremely simple and useful for biologists.

Immune checkpoint therapy has emerged as an effective treatment option for various types of cancers. Key immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and lymphocyte activation gene 3 (LAG-3), have become pivotal targets in cancer immunotherapy. Antibodies designed to inhibit these molecules have demonstrated significant clinical efficacy. Nevertheless, the ability to monitor changes in the immune status of tumors and predict treatment response remains limited. Conventional methods, such as assessing lymphocytes in peripheral blood or conducting tumor biopsies, are inadequate for providing real-time, spatial information about T-cell distributions within heterogeneous tumors. Positron emission tomography (PET) using T-cell specific probes represents a promising and noninvasive approach to monitor both systemic and intratumoral immune changes during treatment. This technique holds substantial clinical significance and potential utility. In this paper, we review the applications of PET probes that target immune cells in molecular imaging.

Programmed death-ligand 1 (PD-L1) expression is related to the efficacy and prognosis in triple-negative breast cancer. This study employed an indirect labeling method to synthesize [¹²⁵I]PI-Atezolizumab. The in vitro stability of [¹²⁵I]PI-Atezolizumab was assessed through incubation in phosphate buffered saline and fetal bovine serum, revealing sustained stability. Specific binding of [¹²⁵I]PI-Atezolizumab to MDA-MB-231 cells expressing humanized PD-L1 was assessed through in vitro incubation, yielding a K_d value comparable to that of Atezolizumab. This suggests that the labeling process did not compromise the affinity of the Atezolizumab to PD-L1. Subsequently, pharmacokinetic studies were conducted in normal mice and biodistribution experiments in tumor-bearing mice. A comparison of the biodistribution results between [¹²⁵I]PI-Atezolizumab and ¹²⁵I-labeled Atezolizumab indicated better in vivo stability for the former. Single photon emission computed tomography (SPECT)/CT imaging further confirmed the targeted specificity of [¹²⁵I]PI-Atezolizumab for PD-L1 in MDA-MB-231 xenografts, which were validated by immunohistochemistry staining. This research underscores the utility of [¹²⁵I]PI-Atezolizumab, prepared via indirect labeling, for monitoring PD-L1 in triple-negative breast cancer models.