Abstract
BackgroundA recent study from our laboratory demonstrated that 11C-LY2428703, a new positron emission tomographic radioligand for metabotropic glutamate receptor 1 (mGluR1), has promising in vitro properties and excellent in vivo performance for imaging rat brain. The present study evaluated 11C-LY2428703 for imaging mGluR1 in monkey and human brains.MethodsRhesus monkeys were imaged at baseline and after administration of an mGluR1 blocking agent to calculate nonspecific binding, as well as after the administration of permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP) blockers to assess whether 11C-LY2428703 is a substrate for efflux transporters at the blood–brain barrier. Human imaging was performed at baseline in three healthy volunteers, and arterial input function was measured.ResultsOverall brain uptake was low in monkeys, though slightly higher in the cerebellum, where mGluR1s are concentrated. However, the uptake was not clearly displaceable in the scans after mGluR1 blockade. Brain penetration of the ligand did not increase after P-gp and BCRP blockade. Brain uptake was similarly low in all human subjects (mean VT with a two-tissue compartment model, 0.093 ± 0.012 mL/cm3) and for all regions, including the cerebellum.ConclusionsDespite promising in vitro and in vivo results in rodents, 11C-LY2428703 was unsuitable for imaging mGluR1s in monkey or human brain because of low brain uptake, which was likely caused by high binding to plasma proteins.
Highlights
A recent study from our laboratory demonstrated that 11C-LY2428703, a new positron emission tomographic radioligand for metabotropic glutamate receptor 1, has promising in vitro properties and excellent in vivo performance for imaging rat brain
We examined factors known to affect the utility of radioligands for brain imaging: blockade of entry into brain by efflux transporters at the blood–brain barrier, the density of the target in brain, the affinity of 11C-LY2428703 for metabotropic glutamate receptor 1 (mGluR1), and binding of the radioligand to plasma proteins
The present study found that 11C-LY2428703 cannot image or quantify mGluR1s in monkey or human brain because of very low brain uptake, largely caused by high binding of the radioligand to plasma proteins
Summary
A recent study from our laboratory demonstrated that 11C-LY2428703, a new positron emission tomographic radioligand for metabotropic glutamate receptor 1 (mGluR1), has promising in vitro properties and excellent in vivo performance for imaging rat brain. From an in vitro perspective, LY2428703 has high affinity for human mGluR1s; after a competition binding assay with 3H-LSN456066, Ki was 2.7 ± 0.5 nM for males and 1.4 ± 0.4 nM for females. LY2428703 has high specific binding to brain homogenates displaceable only by mGluR1 antagonists and no significant affinity for other human mGluRs [10]. An in vivo PET imaging study of rodents expanded this favorable profile; that study found a large specific and displaceable signal in rat cerebellum, insignificant in vivo binding to mGluR5, and negligible accumulation of radiometabolites in brain. LY2428703 was not a substrate for efflux transporters at the blood–brain barrier, as assessed in genetic knockout mice for ABCB1 (permeability glycoprotein (P-gp)) and ABCG2 (breast cancer resistance protein (BCRP)) [10]
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