Quantification of ONO-2952 Occupancy of 18-kDaTranslocator Protein in Conscious Monkey Brains using Positron Emission Tomography

Abstract

We have previously shown that ONO-2952, a novel 18-kDa translocator protein (TSPO) antagonist, inhibits stress-induced accumulation of neurosteroids and noradrenaline release in the rat brain and alleviates the subsequent symptomatic responses with a brain TSPO occupancy of 50% or more. In this study, we measured ONO-2952 brain TSPO occupancy in conscious rhesus monkeys using positron emission tomography (PET) with C-PBR28 as ligand for translational research to clinical application. PET scans were performed after single and repeated oral administration of ONO-2952 at several dose levels for each animal, with sequential arterial blood sampling. In vitro binding studies showed that ONO-2952 potently binds to brain TSPO in monkeys with an affinity equivalent to that in rats. ONO-2952, given orally before PET scans, dose dependently decreasedC-PBR28 uptake without marked brain region specificity. Results of the quantitative analysis using arterial input function revealed that TSPO occupancy after ONO-2952 single and repeated oral administration tended to increase in parallel with its plasma concentration, reaching the highest level of 100%. These findings indicate that ONO-2952 has sufficient brain distribution in primates and that ONO-2952 TSPO occupancy in humans can also be determined using PET.

Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [11C]PBR28

“…The choice to use [ 11 C]PBR28 as the TSPO radiotracer in this study was based on the published literature showing improved signal‐to‐noise ratio with this tracer as well as feasibility studies demonstrating that PBR28 was displaceable by ONO‐2952 in animals (Mitsui et al, ). The current study showed that in the whole brain, ONO‐2952 at a dose of 200 mg demonstrated a mean TSPO occupancy at near saturation (mean 96.3%) with lower TSPO occupancy as the dose decreased (at 6 mg mean occupancy was 59.5%).…”

Sifting through the surfeit of neuroinflammation tracers

“…In one such investigation using the TSPO blocker ONO-2952, the V ND for [ 11 C]PBR28 was 14.2 ml g À1 in brain of non-human primates, indicating a BP ND of approximately 4 in monkey frontal cortex. 122 The recent report of Frankle et al may set a new standard for the quantitation TSPO sites in living human brain. 123 Here, the V T of [ 11 C]PBR28 was measured in brain of healthy volunteers at baseline and after challenge with ONO-2952.…”

“…By applying the Lassen plot, the authors established the V S -to- V ND ratio, calculating a cortical BP ND of 0.5 in MABs and 1.3 in HABs relative to V ND of 2 ml g −1 . 122 This approach has become accessible with the advent of TSPO blockers approved for human use. It is unclear why the Lassen-based V ND and BP ND results differ so greatly between human and non-human primates, or indeed why the human BP ND falls so short of the expectation based on the nearly complete pharmacological blockade of [ 11 C]PBR28 in non-human primates, but there is clearly a need for more displacement studies.…”

In Vivo Receptor Visualization and Evaluation of Receptor Occupancy with Positron Emission Tomography

“…[ 11 C]­DAC ( 3–5.4 ) showed brain transferability in monkeys, and a decrease in the brain PET signal was observed when it was used in combination with nonradioactive PK11195 . Similarly, [ 11 C]­PBR29 ( 3–5.5 ) has been evaluated in monkeys and humans. − Concentration-dependent competitive binding of ONO2965 and 3–5.5 was observed in monkey brain . However, the brain transferability of 3–5.5 in humans was different, suggesting that there are species differences in the expression level and distribution of TSPO.…”

“…264−267 Concentrationdependent competitive binding of ONO2965 and 3−5.5 was observed in monkey brain. 265 However, the brain transferability of 3−5.5 in humans was different, 266 suggesting that there are species differences in the expression level and distribution of TSPO. The TSPO occupancy by ONO2952 in humans determined using 3−5.5 showed dose-dependency between 20−200 mg.…”