Figure 2.

Uptake of [¹¹C]martinostat in rat brain. (A) Timeline schematic of blocking dose administration and PET/CT imaging. All animals were stabilized on anesthesia at least 20 min prior to [¹¹C]martinostat administration. (B) Dynamic tracer uptake in whole brain was evaluated using ROI analysis on dynamic imaging data sets from n = 9 “baseline” rats blocked with vehicle (10% DMSO, 10% Tween 80, 80% saline) 5 min prior to tracer administration. Data are expressed as percent uptake in whole brain relative to uptake at time = 600 s (mean ± standard deviation). (C) Self-blocking of [¹¹C]martinostat tracer binding (change in % of whole brain [¹¹C] uptake) is demonstrated via pretreatment (5 min, iv) with a dose range (0.001–1 mg/kg, n = 1/group or 2.0 mg/kg, n = 3/group) of unlabeled martinostat and compared with baseline controls, described in panel B. (D) Quantification of [¹¹C] activity in whole brain at time 3600 s measured via trend in accumulated radioactivity from time 10 min to time 60 min for baseline (white bar, 0 mg/kg) and each blocking condition (grayscale). (E) Spearman correlation with directional t test identified significant dose–response relationships for relative [¹¹C] blockade in whole brain in rat (gray triangles, r = 0.89; p = 0.006) and whole-brain volume of distribution (V_T) from analogous PET experiments in nonhuman primate (NHP; white squares, r = 0.90; p = 0.042); * indicates blocking doses scaled for NHP equivalent dose (mg/kg). (F) Pretreatment with unlabled martinostat (1 mg/kg) 5 min, 4 h, or 24 h prior to tracer administration demonstrated time-dependent effects of target engagement, calculated as difference from baseline (100% – % blocked binding).