PET radiotracer development for imaging high-affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine-18 labeled aminotetralins in rodents

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• 作者：Jogeshwar Mukherjee ; Divya Majji ; Jasmeet Kaur ; Cristian C. Constantinescu ; Tanjore K. Narayanan ; Bingzhi Shi ; Mohamed T. Nour and Min-Liang Pan
• 刊名：Synapse
• 出版年：2017
• 出版时间：March 2017
• 年：2017
• 卷：71
• 期：3
• 全文大小：1766K
• ISSN：1098-2396

文摘

Imaging the high-affinity, functional state (HA) of dopamine D2 and D3 receptors has been pursued in PET imaging studies of various brain functions. We report further evaluation of ¹⁸F-5-OH-FPPAT, and the newer ¹⁸F-5-OH-FHXPAT and ¹⁸F-7-OH-FHXPAT. Syntheses of ¹⁸F-5-OH-FHXPAT and ¹⁸F-7-OH-FHXPAT were improved by modifications of our previously reported procedures. Brain slices and brain homogenates from male Sprague-Dawley rats were used with the 3 radiotracers (74-111 kBq/cc). Competition with dopamine (1–100 nM) and Gpp(NH)p (10–50 µM) were carried out to demonstrate binding to dopamine D2 and D3 HA-states and binding kinetics of ¹⁸F-5-OH-FPPAT measured. Ex vivo brain slice autoradiography was carried out on rats administered with ¹⁸F-5-OH-FHXPAT to ascertain HA-state binding. PET/CT imaging in rats and wild type (WT) and D2 knock-out mice were carried out using ¹⁸F-7-OH-FHXPAT (2-37 MBq). Striatum was clearly visualized by the three radiotracers in brain slices and dopamine displaced more than 80% of binding, with dissociation rate in homogenates of 2.2 × 10^−2 min^−1 for ¹⁸F-5-OH-FPPAT. Treatment with Gpp(NH)p significantly reduced 50–80% striatal binding with faster dissociation rates (5.0 × 10^−2 min^−1), suggesting HA-state binding of ¹⁸F-5-OH-FPPAT and ¹⁸F-5-OH-FHXPAT. Striatal binding of ¹⁸F-5-OH-FHXPAT in ex vivo brain slices were sensitive to Gpp(NH)p, suggesting HA-state binding in vivo. PET binding ratios of ¹⁸F-7-OH-FHXPAT in rat brain were ventral striatum/cerebellum = 2.09 and dorsal striatum/cerebellum = 1.65; similar binding ratios were found in the D2 WT mice. These results suggest that in vivo PET measures of agonists in the brain at least in part reflect binding to the membrane-bound HA-state of the dopamine receptor.