Development of [¹²³I]IPEB and [¹²³I]IMPEB as SPECT Radioligands for Metabotropic Glutamate Receptor Subtype 5

Abstract

mGlu₅ play an important role in physiology and pathology to various central nervous system (CNS) diseases. Several positron emission tomography (PET) radiotracers have been developed to explore the role of mGlu₅ in brain disorders. However, there are no single photon emission computed tomography (SPECT) radioligands for mGlu₅. Here we report development of [¹²³I]­IPEB ([¹²³I]<b>1</b>) and [¹²³I]­IMPEB ([¹²³I]<b>2</b>) as mGlu₅ radioligands for SPECT. [¹²³I]<b>1</b> and [¹²³I]<b>2</b> were produced by copper­(I) mediated aromatic halide displacement reactions. The SPECT imaging using mouse models demonstrated that [¹²³I]<b>1</b> readily entered the brain and accumulated specifically in mGlu₅-rich regions of the brain such as striatum and hippocampus. However, in comparison to the corresponding PET tracer [¹⁸F]­FPEB, [¹²³I]<b>1</b> showed faster washout from the brain. The binding ratios of the striatum and the hippocampus compared to the cerebellum for [¹²³I]<b>1</b> and [¹⁸F]­FPEB were similar despite unfavorable pharmacokinetics of [¹²³I]<b>1</b>. Further structural optimization of <b>1</b> may lead to more viable SPECT radiotracers for the imaging of mGlu₅