Determination of receptor occupancy in the presence of mass dose: [¹¹C]GSK189254 PET imaging of histamine H₃ receptor occupancy by PF-03654746

Abstract

Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds "tracer" levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant K of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo K. This method was applied in a study of healthy human subjects with the histamine H receptor radioligand [C]GSK189254 to measure the PK-occupancy relationship of the H antagonist PF-03654746. From three test/retest studies, [C]GSK189254 K was estimated to be 9.5 ± 5.9 pM. Oral administration of 0.1 to 4 mg of PF-03654746 resulted in occupancy estimates of 71%-97% and 30%-93% at 3 and 24 h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%-15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H binding sites ( RO = 100%), and its IC was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC was 26% higher.

Cortical stress regulation is disrupted in schizophrenia but not in clinical high risk for psychosis

“…These assumptions are supported experimentally as changes in cortical 11 C-FLB457 binding has not been observed in a dopamine depletion study (Frankle et al, 2010), while $1000% increase of dopamine has been measured with microdialysis following 0.3 mg/kg amphetamine in non-human primates (Narendran et al, 2014). The corrected change in BP ND was calculated as (Gallezot et al, 2017):…”

“…Right and left regions of interest were pooled together to create a single time-activity curve used to derive BP ND . As quantifying 11 C-FLB457 is challenging, in part due to potential mass effects, a novel correction was applied in the current study (Gallezot et al, 2017). The correction takes competition between radioligand and dopamine in the stress condition into account while assuming negligible levels of occupied receptors in the control condition.…”

Exploring occupancy of the histamine H3 receptor by pitolisant in humans using PET

“…GSK189254 and an indirect measurement of K D = 9.5 pM (Gallezot et al, 2017), the corrected "true" occupancy increases 6% points to 90 ± 5%.…”

News and views on in-vivo imaging of neurotransmission using PET and MRI

“…The histamine H3 receptors are presynaptic neuroreceptors that inhibit the release of histamine and other neurotransmitters. There are several H3 receptor tracers under development, e.g., [ 11 C]TASP0410457 44 and [ 11 C]MK-8278 45 ; of which [ 11 C]GSK189254 has recently shown the ability to image and quantify drug-occupancy in man 46 .…”