3-[¹²³I]Iodo-5-(pyridine-2-ylethynyl)benzonitrile ([¹²³I]IPEB): A new SPECT ligand for metabotropic glutamate receptor subtype 5 (mGluR5)

Objectives Recent development of PET radiotracers for mGluR5 enables us to elucidate the role of mGluR5 in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease in vivo. Those successes will bring more demand for mGluR5 radiotracers in the future. However, short half-life of PET isotope and limited number of PET radiochemistry facilities will not be able to catch up with the future demands for mGluR5 research and clinical application. Those problems can be solved by the development of SPECT radiotracers with longer half-life isotopes. Recently several promising iodine compounds were proposed as mGluR5 negative allosteric modulators. Here, we report the radiosynthesis of [¹²³I]IPEB and its preliminary SPECT-CT imaging in normal mouse brain.

Methods Bromo-precursor of [¹²³I]IPEB was prepared by Sonogashira coupling between 2-ethynylpyridine and 3,5-dibromobenzonitrile. The bromine of the precursor was converted into iodine via tributylstannyl group to synthesize nonradioactive IPEB. Radioiodine displacement reaction with [¹²³I]iodide and bromo-precursor mediated by copper(I) catalyst produced [¹²³I]IPEB. SPECT scan was carried out in C57/BL6 mouse model 30 min after administration of [¹²³I]IPEB (300 μCi i.v.) using 4 heads with 16 steps and frame time of 30 sec. SPECT imaging was followed by CT.

Results Bromo-precursor and nonradioactive IPEB were prepared by one step with 64% yield and three step synthesis with overall 23% yield respectively. Radioiodination was completed up to 40% RCY with >98% radiochemical purity. [¹²³I]IPEB did cross BBB, and showed high uptake in striatum, hippocampus, and olfactory bulb corresponding the previous studies with mGluR5 PET radiotracers.

Conclusions We developed promising SPECT radiotracer for mGluR5 with 2-3 steps synthesis. [¹²³I]IPEB displayed high uptake in the brain regions where mGluR5 is abundant. This SPECT ligand will be a promising candidate for translational studies.

Research Support NIBIB-R01EB012864 and NIMH-R01MH91684 to ALB