Synthesis, Biodistribution, and Radiation Dosimetry of a Novel mGluR5 Radioligand: 18F-AZD9272.

Sangram Nag,Mahabuba Jahan,Ryosuke Arakawa,Magnus Schou,Lars Farde,Katarina Varnäs,Christer Halldin

doi:10.1021/acschemneuro.9b00680

Sangram Nag, Mahabuba Jahan + Show 5 more

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https://doi.org/10.1021/acschemneuro.9b00680

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Abstract

The metabotropic glutamate receptor subtype mGluR5 has been proposed as a potential drug target for CNS disorders such as anxiety, depression, Parkinson’s disease, and epilepsy. The AstraZeneca compound AZD9272 has previously been labeled with carbon-11 and used as a PET radioligand for mGluR5 receptor binding. The molecular structure of AZD9272 allows one to label the molecule with fluorine-18 without altering the structure. The aim of this study was to develop a fluorine-18 analogue of AZD9272 and to examine its binding distribution in the nonhuman primate brain in vivo as well as to obtain whole body radiation dosimetry. 18F-AZD9272 was successfully synthesized from a nitro precursor. The radioligand was stable, with a radiochemical purity of >99% at 2 h after formulation in a sterile phosphate buffered solution (pH = 7.4). After injection of 18F-AZD9272 in two cynomolgus monkeys, the maximum whole brain radioactivity concentration was 4.9–6.7% of the injected dose (n = 2) and PET images showed a pattern of regional radioactivity consistent with that previously obtained for 11C-AZD9272. The percentage of parent radioligand in plasma was 59 and 64% (n = 2) at 120 min after injection of 18F-AZD9272, consistent with high metabolic stability. Two whole body PET scans were performed in nonhuman primates for a total of 231 min after injection of 18F-AZD9272. Highest uptakes were seen in liver and small intestine, followed by brain and kidney. The estimated effective dose was around 0.017 mSv/MBq. 18F-AZD9272 shows suitable properties as a PET radioligand for in vivo imaging of binding in the primate brain. 18F-labeled AZD9272 offers advantages over 11C-AZD9272 in terms of higher image resolution, combined with a longer half-life. Moreover, based on the distribution and the estimated radiation burden, imaging of 18F-AZD9272 could be used as an improved tool for quantitative assessment and characterization of AZD9272 binding sites in the human brain by using PET.

Highlights

Glutamate is the brain’s main excitatory neurotransmitter primarily located on the membranes of neuronal and glial cells and is present in over 50% of nervous tissue.[1]
Different solvents such as acetonitrile, DMF, and DMSO were tested at different temperatures (Table 1)
The overall radiosynthesis including the fluorination reaction, HPLC purification, Solid-phase extraction (SPE) isolation, and radiotracer formulation was completed within 70−75 min

Summary

Introduction

Glutamate is the brain’s main excitatory neurotransmitter primarily located on the membranes of neuronal and glial cells and is present in over 50% of nervous tissue.[1]. In 1992, mGluR5 was first cloned in animals and followed by humans several years later.[3] Even though its actions are mostly excitatory,[4] there are strong links and receptor interactions between mGluR5 and the NMDA receptor.[5] It has been reported that the activation of mGluR5 enhances GABA, especially in the nucleus accumbens.[6] The density of mGluR5 is high primarily in the forebrain regions, striatum, and limbic regions.[7,8] the density of mGluR5 is much higher in younger animals than in adults suggests that early intervention targeting the mGluR5 may lead to prevent the neurodevelopmental disorders.[9]

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