Background: In the last decade the development of new PSMA-ligand based radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research. The most promising derivative in terms of interaction with the antigen and clinical properties has been found to be “PSMA-617”, and its lutetium-177 radiolabelled version has recently been approved by EU and USA regulatory agencies for therapeutic purposes. For the above reasons, the development of new derivatives of PSMA-617 radiolabelled with fluorine-18 may still be of great interest. This paper proposes the comparison of two different PSMA-617 derivatives functionalized with NODA and RESCA chelators, respectively, radiolabelled via [¹⁸F]AlF²⁺ complexation. Results: The organic synthesis of two PSMA-617 derivatives and their radiolabelling via [¹⁸F]AlF²⁺ complexation resulted to proceed efficiently and successfully. Moreover, stability in solution and in plasma has been evaluated. The whole radiosynthesis procedure has been fully automated, and the final products have been obtained with radiochemical yield and purity potentially suitable for clinical studies. The biodistribution of the two derivatives was performed both in prostate cancer and glioma tumour models. Compared with the reference [¹⁸F]F-PSMA-1007 and [¹⁸F]F-PSMA-617-RESCA, [¹⁸F]F-PSMA-617-NODA derivative showed a higher uptake in both tumors, faster clearance in non-target organs, and lower uptake in salivary glands. Conclusion: PSMA-617 NODA and RESCA derivatives were radiolabelled successfully via [¹⁸F]AlF²⁺ chelation, the former being more stable in solution and human plasma. Moreover, preclinical biodistribution studies showed that [¹⁸F]F-PSMA-617-NODA might be of potential interest for clinical applications.

Elagolix sodium salt is the first marketed orally active non-peptide gonadotropin-releasing hormone receptor antagonist (GnRHR-ant) for the management of hormone dependent diseases, such as endometriosis and uterine fibroids. Despite its presence on the market since 2018, a thorough NMR analysis of this drug, together with its synthetic intermediates, is still lacking. Hence, with the aim of filling this literature gap, we here performed a detailed NMR investigation, which allowed the complete assignment of the ¹H, ¹³C, and ¹⁵N NMR signals. These data allowed, with the support of the conformational analysis, the determination of the stereochemical profile of the two atropisomers, detectable in solution. Moreover, these latter were also detected by means of cellulose-based chiral HPLC, starting from a sample prepared through an implemented synthetic procedure with respect to the reported ones. Overall, these results contribute to further understanding of the topic of atropisomerism in drug discovery and could be applied in the design of safe and stable analogs, endowed with improved target selectivity.

Introduction: Labeled nanoparticles can be monitored in the body using positron emission tomography (PET) imaging, providing real-time insights into their pharmacokinetics and biodistribution. In the present work, liposomes are labeled with the radionuclide fluorine-18, exploiting a “surface radiolabeling” approach.Methods: Two alkyne-dioleoylphosphatidylethanolamine (DOPE) constructs are embedded within the bulk of the liposome bilayer, which is composed of cholesterol (Ch) and sphingomyelin (SM), and radiolabeling is performed via either a copper(I)-catalyzed cycloaddition “click” reaction (CuAAC) or a cyclooctyne-driven copper-free “click” reaction (CyOctC) modality, using a suitable fluorine-18 labeled azide, obtaining good results in terms of yield, purity, stability, and automation of the entire radiosynthesis process. In addition, radiolabeling is also performed on liposome formulations functionalized with 1) a peptide derived from the receptor-binding domain of apolipoprotein E (mApoE) and 2) a metalloproteinase (MMP)-sensitive lipopeptide (MSLP). The in vivo uptake of these liposomes is evaluated in an orthotopic glioma mouse model (Gli36ΔEGFR cell line) using PET/computed tomography (CT).Results and discussion: The results demonstrate a higher tumor/background ratio, a faster clearance rate, and a lower uptake in healthy brain tissue and peripheral regions for mApoE- and MSLP-functionalized liposomes than for non-functionalized liposomes, prompting further characterization. On the contrary, radiolabeled liposome uptake is higher in the majority of peripheral organs for non-functionalized liposomes. Hence, fluorine-18-labeled liposomes can be reliably used for in vivo PET tracking of multifunctionalized nanoparticles, enabling effective investigation of their potential as drug delivery systems.