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DPA-714, a New Translocator Protein–Specific Ligand: Synthesis, Radiofluorination, and Pharmacologic Characterization

¹ Department of Pharmacology, University of Sydney, Sydney, New South Wales, Australia; ² Department of PET and Nuclear Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; ³ INSERM U619, Tours, France; Université François-Rabelais de Tours, Tours, France; ⁴ CEA, Service Hospitalier Frédéric Joliot, Institut d'Imagerie Biomedicale, Orsay, France; ⁵ Dipartimento di Scienze Farmaceutiche, Università di Firenze, Firenze, Italy; ⁶ Discipline of Medical Radiation Sciences, University of Sydney, Sydney, New South Wales, Australia; ⁷ Brain and Mind Research Institute, University of Sydney, Camperdown, New South Wales, Australia; and ⁸ School of Chemistry, University of Sydney, Sydney, New South Wales, Australia

Correspondence: For correspondence or reprints contact: Michael Kassiou, Brain and Mind Research Institute, 100 Mallett St., Camperdown, New South Wales 2050, Australia. E-mail: M.Kassiou{at}usyd.edu.au

The translocator protein (18 kDa) (TSPO), formerly known as the peripheral benzodiazepine receptor, is dramatically upregulated under pathologic conditions. Activated microglia are the main cell type expressing the TSPO at sites of central nervous system pathology. Radioligands for the TSPO can therefore measure active disease in the brain. This article details the synthesis, radiofluorination, and pharmacologic evaluation of a new TSPO-specific pyrazolopyrimidine, DPA-714. Methods: The affinity of DPA-714 for the TSPO was measured in rat kidney membranes with ³H-PK11195. The in vitro functional activity of DPA-714 was measured in a steroidogenic assay in which the ability of DPA-714 to increase pregnenolone synthesis was measured with rat C6 glioma cells. The radiofluorination of DPA-714 was achieved by nucleophilic ¹⁸F-fluoride displacement of the tosylate precursor. ¹⁸F-DPA-714 was assessed in rats harboring unilateral quinolinic acid (QA) lesions. In addition, pretreatment experiments were performed with PK11195 (5 mg/kg), DPA-714 (1 mg/kg), and DPA-713 (1 mg/kg). The in vivo binding and biodistribution of ¹⁸F-DPA-714 were determined in a baboon with PET. Experiments involving presaturation with PK11195 (1.5 mg/kg) and displacement with DPA-714 (1 mg/kg) were conducted to evaluate the specificity of radioligand binding. Results: In vitro binding studies revealed that DPA-714 displayed a high affinity for the TSPO (dissociation constant, 7.0 nM). DPA-714 stimulated pregnenolone synthesis at levels 80% above the baseline. ¹⁸F-DPA-714 was prepared at a 16% radiochemical yield and a specific activity of 270 GBq/µmol. In rats harboring unilateral QA lesions, an 8-fold-higher level of uptake of ¹⁸F-DPA-714 was observed in the ipsilateral striatum than in the contralateral striatum. Uptake in the ipsilateral striatum was shown to be selective because it was inhibited to the level in the contralateral striatum in the presence of PK11195, nonlabeled DPA-714, or DPA-713. PET studies demonstrated rapid penetration and good retention of ¹⁸F-DPA-714 in the baboon brain. Pretreatment with PK11195 effectively inhibited the uptake of ¹⁸F-DPA-714 in the whole brain, indicating its selective binding to the TSPO. The injection of nonlabeled DPA-714 20 min after the injection of ¹⁸F-DPA-714 resulted in radioligand washout, demonstrating the reversibility of ¹⁸F-DPA-714 binding. Conclusion: ¹⁸F-DPA-714 is a specific radioligand for the TSPO, displaying promising in vivo properties and thus warranting further investigation.

Key Words: PET • translocator protein • ¹⁸F • DPA-714 • microglia

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