Synthesis, ³H‐labelling and in vitro evaluation of a substituted dipiperidine alcohol as a potential ligand for chemokine receptor 2

Abstract

The immune system is implicated in the pathology of neurodegenerative disorders. The C‐C chemokine receptor 2 (CCR2) is one of the key targets involved in the activation of the immune system. A suitable ligand for CCR2 could be a useful tool to study immune activation in central nervous system (CNS) disorders. Herein, we describe the synthesis, tritium radiolabelling, and preliminary in vitro evaluation in post‐mortem human brain tissue of a known potent small molecule antagonist for CCR2. The preparation of a tritium‐labelled analogue for the autoradiography (ARG) study gave rise to an intriguing and unexpected side reaction profile through a novel amination of ethanol and methanol in the presence of tritium. After successful preparation of the tritiated radioligand, in vitro ARG measurements on human brain sections revealed nonspecific binding properties of the selected antagonist in the CNS.

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

“…Indeed, following the concept of classic halogen chemistry, deuteration can be easily achieved with controlled regioselectivity. In analogy to hydrogenation chemistry, dehalogenative deuteration or tritiation is frequently carried out using a heterogeneous palladium catalyst (Pd/C) along with deuterium or tritium gas. − However, protic hydrogen atoms in the substrate or solvent quickly exchange with the isotope source under these conditions, leading to drastically reduced degrees of labeling. Consequently, exchange of all labile protons prior to reduction as well as the use of dry and potentially deuterated solvents are required.…”

“…As shown in Scheme , a tritiated radioligand was prepared by Artelsmair and co-workers . First, the indole moiety of precursor a was iodinated using N-iodosuccinimide (NIS) and TFA in DCM, yielding compound b .…”

“…400 As shown in Scheme 152, a tritiated radioligand was prepared by Artelsmair and co-workers. 401 First, the indole moiety of precursor a was iodinated using N-iodosuccinimide (NIS) and TFA in DCM, yielding compound b. Subsequent hydrogenation utilizing tritium gas at low pressure (approximately 50 mbar) provided in short times (15 min and 1 h) the tritium-labeled product c without affecting the olefinic double bond.…”

The Future of (Radio)‐Labeled Compounds in Research and Development within the Life Science Industry

“…However, establishing an own (in‐house) fully equipped PET facility including all necessary infrastructure (cyclotron, hot cells, synthesis modules, dispensing units) is not the preferred option for a pharma company. To speed up the PET tracer development process while simultaneously minimizing operational costs, the most pragmatic and reasonable strategy is to first identify and characterize tritium‐labeled radioligands of high affinity and selectivity before the potentially “best” tracer candidates (or precursors thereof, respectively) will be submitted to external PET centers for labelling them with carbon‐11 or fluorine‐18 [28,40,41,42] …”

Die Zukunft (Radio‐)‐isotopenmarkierter Verbindungen in Forschung und Entwicklung der modernen Lebenswissenschaften

“…deren Vorläufer) an externe PET-Zentren zur Markierung mit Kohlenstoff-11 oder Fluor-18 weitergeleitet werden. [28,40,41,42] Kürzlich wurden PET-Tracer in der Diabetesforschung eingesetzt, um die Targetbelegung von dualen Rezeptor-Agonisten des Glucagon-ähnlichen Peptid-1/Glucagon (GLP-1/GCG) Rezeptors zu untersuchen (Abbildung 4). Der Glucagon-Rezeptor (GCGR) ist ein wichtiges Target in der antidiabetischen Therapie, insbesondere in Kombination mit der Pharmakologie von Glucagon-ähnlichen Peptid-1 Rezeptor-Agonisten.…”