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Objective:
Multiple PET ligands exist for imaging metabotropic glutamate receptor subtype 5 (mGluR5). The selection of best PET ligand to image mGluR5 is necessary for a larger clinical study in patient population but choosing such a ligand is likely difficult because the radioligands are evaluated under different conditions and in different subject populations.
The purpose of this study is to determine the best PET ligand for imaging mGluR5 receptors in brain of healthy subjects. This will be accomplished by measuring mGluR5 receptor occupancy in the same subject using two PET ligands having high affinity at mGluR5 [(11)C]SP203 and [(11)C]FPEB, and using STX107, a negative allosteric modulator at mGluR5 receptors to block the radioligand brain uptake. The two radioligands were chosen among many based on the recommendation from the mGluR5 working group. Two serial PET scans using [(11)C]SP203 and [(11)C]FPEB will be performed under baseline condition on one day and under receptor blocked condition on another day. As [(11)C]FPEB has not been evaluated in humans before, we plan to acquire brain and whole-body dosimetry scans before measuring receptor occupancy.
Furthermore, we wish to compare FPEB labeled with (11)C and (18)F in the same subject -two brain PET scans using [(11)C]FPEB and [(18)F]FPEB will be done serially in the same subject on the same day. FPEB labeled with (11)C has the same structure as FPEB labeled with (18)F and is therefore expected to yield similar binding measures.
Study population:
55 healthy volunteers aged 18 to 55 years.
Design:
To characterize brain uptake and distribution of radioligand, an initial cohort of healthy volunteers (n = up to 10) will undergo brain PET scans using [(11)C]FPEB. To estimate radiation absorbed doses for [(11)C]FPEB, a cohort of healthy volunteers (n = up to 10) will undergo whole-body PET or PET/CT scans. A subsequent cohort of healthy volunteers (n = up to 15) will have two scanning sessions: a) baseline i.e., medication-free and b) blocking i.e. with medication. Each scanning session will be with two serial PET scans: [(11)C]FPEB and [(11)C]SP203 in a day (scans in morning and afternoon). The blocking session will be after administration of STX107, at which time we will also measure the concentration of STX107 in plasma. Both scanning sessions would include an arterial line and measurement of the input function of parent radioligand separated from radiometabolites as well as plasma free fraction of radioligand. We plan to study up to two doses of STX107, with three to five subjects at each dose. The blockade of brain uptake of [(11)C]FPEB and [(11)C]SP203 will be plotted as a function of the plasma concentration of STX107. A further cohort of healthy volunteers (n = up to 15) will undergo two serial brain PET scans with [(11)C]FPEB and [(18)F]FPEB in the same day (one scan in the morning, and the other in the afternoon).
Outcome measures:
The radioligands will be evaluated on three criteria:
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