PET radiotracer development for imaging high-affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine-18 labeled aminotetralins in rodents
| Autor: | Cristian Constantinescu, Divya Majji, Jogeshwar Mukherjee, Bingzhi Shi, Tanjore K. Narayanan, Jasmeet Kaur, Mohamed T. Nour, Min-Liang Pan |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Fluorine Radioisotopes medicine.medical_specialty Tetrahydronaphthalenes Striatum Article Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Slice preparation In vivo Dopamine Internal medicine Dopamine receptor D2 medicine Animals Receptors Dopamine D2 Chemistry Receptors Dopamine D3 Brain Receptor–ligand kinetics Rats 030104 developmental biology Endocrinology Dopamine receptor Positron-Emission Tomography Radiopharmaceuticals 030217 neurology & neurosurgery Ex vivo medicine.drug |
| Zdroj: | Synapse. 71:e21950 |
| ISSN: | 0887-4476 |
| DOI: | 10.1002/syn.21950 |
| Popis: | 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 (1nM to 100nM) and Gpp(NH)p (10-50µM) 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 (KO) 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 2.2x10−2 min−1 for 18F-5-OH-FPPAT. Treatment with Gpp(NH)p significantly reduced 50-80% striatal binding with faster dissociation rates (5.0x10−2 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. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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