Synthesis, radiolabelling and in vitro andin vivo evaluation of a novel fluorinated ABP688 derivativefor the PET imaging of metabotropic glutamate receptor subtype 5

American Journal of Nuclear Medicine and Molecular Imaging

Linjing Mu¹  Stefanie D Krämer¹  Dominique S Leutwiler¹  Patrick Dennler¹  Cindy A Wanger-Baumann¹  Simon M Ametamey¹  Selena Milicevic Sephton¹  Roger Schibli¹ 

关键词: mGluR5;    PET imaging;    [18F]-PSS223;    [11C]-ABP688;    [18F]-FDEGPECO;    autoradiography;    microsome enzymes;   

DOI  :  

学科分类：过敏症与临床免疫学

来源: e-Century Publishing Corporation

【 摘 要 】

(E)-3-(Pyridin-2-ylethynyl)cyclohex-2-enoneO-(2-(3-¹⁸F-fluoropropoxy)ethyl) oxime([¹⁸F]-PSS223) was evaluated in vitro andin vivo to establish its potential as a PET tracer forimaging metabotropic glutamate receptor subtype 5 (mGluR5).[¹⁸F]-PSS223 was obtained in 20% decay corrected radiochemical yieldwhereas the non-radioactive PSS223 was accomplished in 70% chemical yield in aS_N2 reaction of common intermediate mesylate 8 with potassiumfluoride. The in vitro binding affinity of[¹⁸F]-PSS223 was measured directly in a Scatchard assay to giveK_d = 3.34 ± 2.05 nM. [¹⁸F]-PSS223 was stable inPBS and rat plasma but was significantly metabolized by rat liver microsomalenzymes, but to a lesser extent by human liver microsomes. Within 60 min, 90%and 20% of [¹⁸F]-PSS223 was metabolized by rat and human microsomeenzymes, respectively. In vitro autoradiography on horizontalrat brain slices showed heterogeneous distribution of [¹⁸F]-PSS223with the highest accumulation in brain regions where mGluR5 is highly expressed(hippocampus, striatum and cortex). Autoradiography in vitrounder blockade conditions with ABP688 confirmed the high specificity of[¹⁸F]-PSS223 for mGluR5. Under the same blocking conditions butusing the mGluR1 antagonist, JNJ16259685, no blockade was observed demonstratingthe selectivity of [¹⁸F]-PSS223 for mGluR5 over mGluR1. Despitefavourable in vitro properties of [¹⁸F]-PSS223, aclear-cut visualization of mGluR5-rich brain regions in vivo inrats was not possible mainly due to a fast clearance from the brain and lowmetabolic stability of [¹⁸F]-PSS223.

【 授权许可】

Unknown