Comparison of two PET radioligands, [¹¹C]FPEB and [¹¹C]SP203, for quantification of metabotropic glutamate receptor 5 in human brain

Of the two ¹⁸F-labeled PET ligands currently available to image metabotropic glutamate receptor 5 (mGluR5), [¹⁸F]FPEB is reportedly superior because [¹⁸F]SP203 undergoes glutathionlyation, generating [¹⁸F]-fluoride ion that accumulates in brain and skull. To allow multiple PET studies on the same day with lower radiation exposure, we prepared [¹¹C]FPEB and [¹¹C]SP203 from [¹¹C]hydrogen cyanide and compared their abilities to accurately quantify mGluR5 in human brain, especially as regards radiometabolite accumulation. Genomic plot was used to estimate the ratio of specific-to-nondisplaceable uptake (BP_ND) without using a receptor blocking drug. Both tracers quantified mGluR5; however [¹¹C]SP203, like [¹⁸F]SP203, had radiometabolite accumulation in brain, as evidenced by increased distribution volume (V_T) over the scan period. Absolute V_T values were ∼30% lower for ¹¹C-labeled compared with ¹⁸F-labeled radioligands, likely caused by the lower specific activities (and high receptor occupancies) of the ¹¹C radioligands. The genomic plot indicated ∼60% specific binding in cerebellum, which makes it inappropriate as a reference region. Whole-body scans performed in healthy subjects demonstrated a low radiation burden typical for ¹¹C-ligands. Thus, the evidence suggests that [¹¹C]FPEB is superior to [¹¹C]SP203. If prepared in higher specific activity, [¹¹C]FPEB would presumably be as effective as [¹⁸F]FPEB for quantifying mGluR5 in human brain.