Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Lohith TG

PROVIDER: S-EPMC5531344 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Lohith Talakad G TG Tsujikawa Tetsuya T Siméon Fabrice G FG Veronese Mattia M Zoghbi Sami S SS Lyoo Chul Hyoung CH Kimura Yasuyuki Y Morse Cheryl L CL Pike Victor W VW Fujita Masahiro M Innis Robert B RB

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20160101 7

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 abiliti ...[more]

PMID: 27629098

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Project description:Selective modulation of metabotropic glutamate receptor 2 (mGlu2) represents a novel therapeutic approach for treating brain disorders, including schizophrenia, depression, Parkinson's disease (PD), Alzheimer's disease (AD), drug abuse and addiction. Imaging mGlu2 using positron emission tomography (PET) would allow for in vivo quantification under physiological and pathological conditions and facilitate drug discovery by enabling target engagement studies. In this paper, we aimed to develop a novel specific radioligand derived from negative allosteric modulators (NAMs) for PET imaging of mGlu2. Methods. A focused small molecule library of mGlu2 NAMs with tetrahydro naphthyridine scaffold was synthesized for pharmacology and physicochemical evaluation. GIRK dose-response assays and CNS panel binding selectivity assays were performed to study the affinity and selectivity of mGlu2 NAMs, among which compounds 14a and 14b were selected as PET ligand candidates. Autoradiography in SD rat brain sections was used to confirm the in vitro binding specificity and selectivity of [11C]14a and [11C]14b towards mGlu2. In vivo binding specificity was then studied by PET imaging. Whole body biodistribution study and radiometabolite analysis were conducted to demonstrate the pharmacokinetic properties of [11C]14b as most promising PET mGlu2 PET ligand. Results. mGlu2 NAMs 14a-14g were synthesized in 14%-20% yields in five steps. NAMs 14a and 14b were selected to be the most promising ligands due to their high affinity in GIRK dose-response assays. [11C]14a and [11C]14b displayed similar heterogeneous distribution by autoradiography, consistent with mGlu2 expression in the brain. While PET imaging study showed good brain permeability for both tracers, compound [11C]14b demonstrated superior binding specificity compared to [11C]14a. Further radiometabolite analysis of [11C]14b showed excellent stability in the brain. Conclusions. Compound 14b exhibited high affinity and excellent subtype selectivity, which was then evaluated by in vitro autoradiography and in vivo PET imaging study after labeling with carbon-11. Ligand [11C]14b, which we named [11C]MG2-1904, demonstrated high brain uptake and excellent in vitro/in vivo specific binding towards mGlu2 with high metabolic stability in the brain. As proof-of-concept, our preliminary work demonstrated a successful example of visualizing mGlu2in vivo derived from NAMs, which represents a promising chemotype for further development and optimization aimed for clinical translation.

Dataset Information

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

Publications

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

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