Synthesis and characterization in monkey of [11C]SP203 as a radioligand for imaging brain metabotropic glutamate 5 receptors

Purpose

[¹⁸F]SP203 (3-fluoro-5-(2-(2-([¹⁸F]fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile) is an effective high-affinity and selective radioligand for imaging metabotropic 5 receptors (mGluR5) in human brain with PET. To provide a radioligand that may be used for more than one scanning session in the same subject in a single day, we set out to label SP203 with shorter-lived ¹¹C (t _1/2?=?20.4?min) and to characterize its behavior as a radioligand with PET in the monkey.

Methods

Iodo and bromo precursors were obtained by cross-coupling 2-fluoromethyl-4-((trimethylsilyl)ethynyl)-1,3-thiazole with 3,5-diiodofluorobenzene and 3,5-dibromofluorobenzene, respectively. Treatment of either precursor with [¹¹C]cyanide ion rapidly gave [¹¹C]SP203, which was purified with high-performance liquid chromatography. PET was used to measure the uptake of radioactivity in brain regions after injecting [¹¹C]SP203 intravenously into rhesus monkeys at baseline and under conditions in which mGluR5 were blocked with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP). The emergence of radiometabolites in monkey blood in vitro and in vivo was assessed with radio-HPLC. The stability of [¹¹C]SP203 in human blood in vitro was also measured.

Results

The iodo precursor gave [¹¹C]SP203 in higher radiochemical yield (>98?%) than the bromo precursor (20–52?%). After intravenous administration of [¹¹C]SP203 into three rhesus monkeys, radioactivity peaked early in brain (average 12.5?min) with a regional distribution in rank order of expected mGluR5 density. Peak uptake was followed by a steady decline. No radioactivity accumulated in the skull. In monkeys pretreated with MTEP before [¹¹C]SP203 administration, radioactivity uptake in brain was again high but then declined more rapidly than in the baseline scan to a common low level. [¹¹C]SP203 was unstable in monkey blood in vitro and in vivo, and gave predominantly less lipophilic radiometabolites. By contrast, [¹¹C]SP203 was stable in human blood in vitro.

Conclusion

[¹¹C]SP203 emulates [¹⁸F]SP203 with regard to providing a sizeable mGluR5-specific signal in monkey brain, and advantageously avoids troublesome accumulation of radioactivity in bone. Although [¹¹C]SP203 is unsuitable for mGluR5 quantification in monkey brain, its evaluation as a PET radioligand for studying human brain mGluR5 is nevertheless warranted.