Late-Stage Carbon-14 Labeling and Isotope Exchange: Emerging Opportunities and Future Challenges.

Carbon-14 (14C) is a gold standard technology routinely utilized in pharmaceutical and agrochemical industries for tracking synthetic organic molecules and providing their metabolic and safety profiles. While the state of the art has been dominated for decades by traditional multistep synthetic approaches, the recent emergence of late-stage carbon isotope labeling has provided new avenues to rapidly access carbon-14-labeled biologically relevant compounds. In particular, the development of carbon isotope exchange has represented a fundamental paradigm change, opening the way to unexplored synthetic transformations. In this Perspective, we discuss the recent developments in the field with a critical assessment of the literature. We subsequently discuss research directions and future challenges within this rapidly evolving field.

Monitoring In Vivo Performances of Protein-Drug Conjugates Using Site-Selective Dual Radiolabeling and Ex Vivo Digital Imaging.

In preclinical models, the development and optimization of protein-drug conjugates require accurate determination of the plasma and tissue profiles of both the protein and its conjugated drug. To this aim, we developed a bioanalytical strategy based on dual radiolabeling and ex vivo digital imaging. By combining enzymatic and chemical reactions, we obtained homogeneous dual-labeled anti-MMP-14 Fabs (antigen-binding fragments) conjugated to monomethyl auristatin E where the protein scaffold was labeled with carbon-14 (14C) and the conjugated drug with tritium (3H). These antibody-drug conjugates with either a noncleavable or a cleavable linker were then evaluated in vivo. By combining liquid scintillation counting and ex vivo dual-isotope radio-imaging, it was possible not only to monitor both components simultaneously during their circulation phase but also to quantify accurately their amount accumulated within the different organs.

A general procedure for carbon isotope labeling of linear urea derivatives with carbon dioxide.

Carbon isotope labeling is a traceless technology, which allows tracking the fate of organic compounds either in the environment or in living organisms. This article reports on a general approach to label urea derivatives with all carbon isotopes, including 14C and 11C, based on a Staudinger aza-Wittig sequence. It provides access to all aliphatic/aromatic urea combinations.

Investigation by mass spectrometry and 32P post-labelling of DNA adducts formation from 1,2-naphthoquinone, an oxydated metabolite of naphthalene.

Naphthalene is the simplest representative of polycyclic aromatic hydrocarbons (PAHs). It is detected as major pollutant in the different compartments of the environment. This compound is considered by the international agency for research on cancer (IARC), the specialized cancer agency of the World Health Organisation (WHO), as a possible carcinogenic (group 2B) since 2002, mainly based on studies on chronic inhalation in rodent by the national toxicology program of the U.S. department of health and human services. In humans, its main metabolites correspond to derivatives substituted in position and 1 and 2 as 1,2-naphthoquinone (1,2-NphQ). Based on previous studies, 1,2-NphQ is supposed to react with DNA to form mostly depurinating adducts, a possible initiating step of carcinogenicity. To confirm this potentiality, adducts were synthetized by the reaction of 1,2-NphQ with 2'-deoxyguanosine (2'-dG) in N,N-dimethylformamide (DMF), water and calf thymus DNA. 2'-dG adducts were analyzed by 32P post-labelling, HPLC with ultra-violet detection and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). We found stable DNA adducts detected in DNA. We proposed a formation mechanism by a 1,4-Michael addition with 2'-dG. Adducts with 2'-deoxyxanthosine are formed after a spontaneous deamination of 2'-dG. These adducts are good candidates as biomarkers allowing evaluation of exposure to naphthalene and its derivatives in the development of pathologies such as cancer.

Recent Advances in Synthetic Methods for Radioiodination.

Organic compounds bearing radioisotopes of iodine are widely used for biological research, diagnostic imaging, and radiotherapy. Early reported synthetic methods for the incorporation of radioiodine have generally involved high temperature reactions or strongly oxidizing conditions. To overcome these limitations and to cope with the demand for novel radioiodinated probes, there has been a surge in the development of new synthetic methodology for radioiodination. This synopsis describes the key transformations developed recently.

Design of iodinated radioligands for SPECT imaging of central human 5-HT4R using a ligand lipophilicity efficiency approach.

A series of iodinated ligands for the SPECT imaging of 5-HT4 receptors was designed starting from the previously reported hit MR-26132. We focused on the modulation of the piperidine-containing lateral chain by introducing hydrophilic groups in order to decrease the liphophilicity of the new ligands. All the synthesized compounds were tested for their binding affinities on 5-HT4Rs and based on the Ligand Lipophilicity Efficiency approach, compound 13 was further selected for radioiodination with iodine-125 and imaging experiments. Compound 13 showed its ability to displace the specific signal of the reference compound [125I]SB-207710 but no significant detection of [125I]13 was observed in vivo in SPECT experiments.

Characteristics of Pediatric Dentists Who Work When Sick.

Purpose: Presenteeism, or working while sick, results in loss of productivity and risk of spreading disease. The purpose of the present study was to identify current work practices and beliefs related to presenteeism, including demographic and practice factors that may significantly relate to presenteeism among practicing dentists in the United States. Methods: A survey of American Academy of Pediatric Dentistry members assessed dentists' practices and beliefs regarding presenteeism. Data were analyzed using descriptive statistics, chi-square test, and multi-variate logistic regression. Results: Most respondents (86 percent) worked at least once while sick in the last year. Years in practice, region, and student debt level were significantly associated with presenteeism after adjusting for confounders. Reasons for presenteeism were related to practice type, gender, years in practice, region, and salary type. Conclusions: The majority of pediatric dentists treat patients while sick. Pediatric dentists are influenced to practice while sick due to perceived economic and social pressures, including meeting expectations of colleagues and patients.

Palladium-Mediated Site-Selective C-H Radio-iodination.

The palladium-mediated C-H radio-iodination of arenes using sodium iodide as the primary isotopic source is reported and performed without chemical know-how in 30 min and applied to the synthesis of complex radio-iodinated compounds of biological interest.