Real-time LB-102 target engagement using [¹¹C]Raclopride PET

Objectives: Schizophrenia is a debilitating disease affecting ~1% of the population. LB-102 is a novel benzamide selective D₂/D₃ agonist designed to improve blood brain barrier (BBB) permeability of amisulpride, a well-established dopamine antagonist used to treat schizophrenia in Europe. The objective of this study is to develop a translational method of non-invasively quantifying real-time target engagement by LB-102 that can be used in early phase clinical trials.

Methods: BALB/c mice (n=4) were administered LB-102 (100mg/kg) by oral gavage approximately 140 minutes prior to i.v. injection of [¹¹C]Raclopride and subsequent microPET imaging. A control group (n=4) was scanned without prior blocking. Static Images were acquired 20-50 minutes post tracer injection on a Siemens Inveon microPET scanner and co-registered with a microCT (MILabs). Specific binding values were obtained by subtracting the cerebellar reference region in LB-102 treated and untreated mice. Data is presented as a percentage of [¹¹C]Raclopride uptake blocked by LB-102 pretreatment.

Results: Significant reduction of [¹¹C]Raclopride uptake in the striatum (68%) was achieved in the treated group following the administration of LB-102 compared to a robust striatal activity in the control untreated mice. [¹¹C]Raclopride accumulation was specific to the striatal region without any significant uptake in other brain tissues (20:1 ratio to cerebellum in the control group).

Conclusions: [¹¹C]Raclopride PET imaging of LB-102 D₂ receptor binding is a translational method to quantitatively evaluate real-time target engagement of the D₂ receptor that can be used in early phase dose finding studies as a companion to disease symptom endpoints. This is significant because quantitative PET imaging provides an objective means to assess drug actions that can add value to the more subjective clinical endpoints typically used in schizophrenia drug development. Support: Study was sponsored by LB Pharmaceuticals Inc. The PET early drug development program is supported by the Columbia Dept. of Radiology and Irving Institute CTSA Translational Therapeutics Accelerator (UL1TR001873).