AJNMMI Copyright © 2011-present, All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711, USA
Am J Nucl Med Mol Imaging 2012;2(1):14-28.

Original Article
Synthesis, radiolabelling and in vitro and in vivo evaluation of a novel fluorinated
ABP688 derivative for the PET imaging of metabotropic glutamate receptor
subtype 5

Selena Milicevic Sephton, Patrick Dennler, Dominique S Leutwiler, Linjing Mu, Cindy A Wanger-Baumann, Roger Schibli, Stefanie D
Krämer, Simon M Ametamey

Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Department of Chemistry and Applied Biosciences of ETH Zurich,
Wolfgang-Pauli Strasse 10, 8093 Zurich, Switzerland; Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Department of
Nuclear Medicine, University Hospital Zurich, Switzerland

Received November 6, 2011; accepted November 20, 2011; Epub December 10, 2011; Published January 1, 2011

Abstract: (E)-3-(Pyridin-2-ylethynyl)cyclohex-2-enone O-(2-(3-18F-fluoropropoxy)ethyl) oxime ([18F]-PSS223) was evaluated in vitro
and in vivo to establish its potential as a PET tracer for imaging metabotropic glutamate receptor subtype 5 (mGluR5). [18F]-PSS223
was obtained in 20% decay corrected radiochemical yield whereas the non-radioactive PSS223 was accomplished in 70% chemical
yield in a SN2 reaction of common intermediate mesylate 8 with potassium fluoride. The in vitro binding affinity of [18F]-PSS223 was
measured directly in a Scatchard assay to give Kd = 3.34 ± 2.05 nM. [18F]-PSS223 was stable in PBS and rat plasma but was
significantly metabolized by rat liver microsomal enzymes, but to a lesser extent by human liver microsomes. Within 60 min, 90% and
20% of [18F]-PSS223 was metabolized by rat and human microsome enzymes, respectively. In vitro autoradiography on horizontal rat
brain slices showed heterogeneous distribution of [18F]-PSS223 with the highest accumulation in brain regions where mGluR5 is
highly expressed (hippocampus, striatum and cortex). Autoradiography in vitro under blockade conditions with ABP688 confirmed the
high specificity of [18F]-PSS223 for mGluR5. Under the same blocking conditions but using the mGluR1 antagonist, JNJ16259685,
no blockade was observed demonstrating the selectivity of [18F]-PSS223 for mGluR5 over mGluR1. Despite favourable in vitro
properties of [18F]-PSS223, a clear-cut visualization of mGluR5-rich brain regions in vivo in rats was not possible mainly due to a fast
clearance from the brain and low metabolic stability of [18F]-PSS223.
(ajnmmi1111002).

Keywords: MGluR5, PET imaging, [18F]-PSS223, [11C]-ABP688, [18F]-FDEGPECO, autoradiography, microsome enzymes

Full text PDF

Address all correspondence to:
Dr. Simon M Ametamey
Center for Radiopharmaceutical Sciences of ETH, PSI and USZ
Department of Chemistry and Applied Biosciences of ETH Zurich
Wolfgang-Pauli Strasse 10, 8093 Zurich, Switzerland.
Tel: +41 44 6337463; Fax: +41 44 6331367
E-mail: simon. ametamey@ pharma.ethz.ch