Efficient tritiation of the translocator protein (18 kDa) selective ligand DPA‐714. (January 2015)

• Record Type: Journal Article
• Authors: Damont, Annelaure; Garcia‐Argote, Sébastien; Buisson, David‐Alexandre; Rousseau, Bernard; Dollé, Frédéric
• Is Part Of: Journal of labelled compounds & radiopharmaceuticals. Volume 58:Number 1(2015)
• Page Start: 1
• Page End: 6
• Publication Date: 2015-01
• Subjects: Tracers (Chemistry) -- Periodicals; Radiopharmaceuticals -- Periodicals; 615.8424
• DOI: 10.1002/jlcr.3252
• Languages: English
• ISSNs: 0362-4803

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>DPA‐714 (<italic>N</italic>, <italic>N</italic>‐diethyl‐2‐(2‐(4‐(2‐fluoroethoxy)phenyl)‐5, 7‐dimethylpyrazolo[1, 5‐a]pyrimidin‐3‐yl)acetamide) is a recently discovered fluorinated ligand of the translocator protein 18 kDa (TSPO). Labelled with the short‐lived positron emitter fluorine‐18, this structure is today the radioligand of reference for <italic>in vivo</italic> imaging of microglia activation and neuroinflammatory processes with positron emission tomography. In the present work, an isotopically tritium‐labelled version was developed ([<sup>3</sup>H]DPA‐714), in order to access high resolution <italic>in vitro</italic> and <italic>ex vivo</italic> microscopic autoradiography studies, repeated and long‐lasting receptor binding studies and <italic>in vivo</italic> pharmacokinetic determination at late time points. Briefly, DPA‐714 as reference, and its 3, 5‐dibrominated derivative as precursor for labelling, were both prepared from DPA‐713 in nonoptimized 32% (two steps) and 10% (three steps) yields, respectively. Reductive debromination using deuterium gas and Pd/C as catalyst in methanol, performed at the micromolar scale, confirmed the regioselective introduction of two deuterium atoms at the meta positions of the phenyl ring. Tritiodebromination was analogously performed using no‐carrier tritium gas. HPLC purification provided >96% radiochemically pure [<sup>3</sup>H]DPA‐714 (7 GBq) with a 2.1 TBq/mmol specific radioactivity. Interestingly, additional hydrogen‐for‐tritium exchanges were also observed at the 5‐methyl and 7‐methyl positions of the pyrazolo[1, 5‐a]pyrimidine, opening novel perspectives in the labelling of compounds featuring this heterocyclic core.</p> </abstract>