Abstract
1021
Objectives: Histone deacetylase 6 (HDAC6) regulates microtubule stability and function. Dysregulation is associated with certain cancers and several central nervous system disorders including Alzheimer's and Parkinson's diseases, and major depressive disorder (1,2). Thus, HDAC6 modulation holds therapeutic potential. Previously, a novel radiotracer [18F]Bavarostat (brain penetrant HDAC6 inhibitor with excellent selectivity) was developed (3). This study aims to apply [18F]Bavarostat in nonhuman primates to 1) perform radiation dosimetry calculations, and 2) determine the appropriate tracer kinetic model for quantification of brain imaging data.
Methods: Whole body PET scan were performed on the Siemens mCT scanner in four rhesus monkeys (2 male, 2 female) to measure organ radiation dose. Three additional monkeys underwent brain PET imaging on the Focus-220 scanner with 180 min of dynamic scans and metabolite-corrected input functions. In one subject, a HDAC6 selective inhibitor (ACY-775, IC50: 7.5 nM, 2 mg/kg) was administered prior to tracer injection to assess specific binding of [18F]Bavarostat. Regional distribution volume (VT) was calculated using one- and two-tissue compartment models (1TC and 2TC) as well as the multilinear analysis-1 method.
Results: Injected activity in the dosimetry scans was 169.9 ± 12.7 MBq (0.84 ± 0.60 µg injected mass, n = 4). For males, highest uptake was observed in the liver, followed by the testes and the gallbladder wall, with the testes as the dose-limiting organ with a single study dose limit of 413 MBq (Fig. 1). When applied to the 55 kg adult female phantom, liver is the critical organ, with a 309 MBq single study dose limit. For the brain scans, injected activity was 175.5 ± 10.7 MBq (0.70 ± 0.11 µg injected mass, n = 3). [18F]Bavarostat was metabolized fairly slowly, with 52 ± 18% parent fraction at 30 min, 29 ± 9% at 90 min, 19 ± 5% at 120 min, and 14 ± 3% at 180 min post-injection (n = 3). Plasma free fraction (fp) was 0.05 ± 0.02 (n = 3). [18F]Bavarostat displayed high brain uptake and relatively slow kinetics (Fig. 2), with regional tracer uptake highest in the occipital cortex followed by putamen and cerebellum, and lowest in centrum semiovale (CS). Regional time-activity curves were well fitted by all models. Baseline K1 values (mL/cm3/min, Table 1) from 1TC ranged from 0.17 (CS) to 0.58 in the occipital cortex. Baseline 1TC VT values (mL/cm3) ranged from 35.0 (CS) to 100.8 in nucleus accumbens (NAcc). Baseline VT values showed less than 5% difference in nearly all regions with a 120 min scan duration compared with the 180 min full scan duration. In the preblocked subject, 1TC VT values were 43% lower in NAcc, 28% lower on average in gray matter regions, and 5% lower in CS. Using the occupancy plot, 58.9% blockade was estimated with the administered ACY-775 dose, and calculated VND was 31.2 mL/cm3. Based on this VND, regional baseline BPND values were calculated and ranged from 2.2 (NAcc) to 0.1 (CS).
Conclusions: Based on this study, [18F]Bavarostat appears to demonstrate reasonable tracer characteristics in nonhuman primates: fast and high brain uptake, tissue kinetics appropriate for quantification, and good specific binding signals. The 1TC model appears suitable for describing the kinetics. The blocking experiment suggests that [18F]Bavarostat has good selectivity to HDAC6. Altogether, [18F]Bavarostat appears to be a good radiotracer for HDAC6 mapping and quantification. References: (1) Hubbert C, Guardiola A, Shao R, et al. HDAC6 is a microtubule-associated deacetylase. Nature. 2002;417:455-458. (2) Anderson KW, Chen J, Wang M, Mast N, Pikuleva IA, Turko I V. Quantification of histone deacetylase isoforms in human frontal cortex, human retina, and mouse brain. PLoS One. 2015;10:e0126592. (3) Strebl MG, Campbell AJ, Zhao WN, et al. HDAC6 Brain Mapping with [18F]Bavarostat Enabled by a Ru-Mediated Deoxyfluorination. ACS Cent Sci. 2017;3:1006-1014.