Evaluation of the novel radiotracer ¹⁸F-DBT-10 for imaging the α₇ nicotinic acetylcholine receptor in non-human primates

Objectives: The α₇nAChR is involved in cognition and a potential drug target for treatment of Alzheimer’s disease and schizophrenia. ¹⁸F-DBT-10 is a candidate radioligand for α₇nAChR imaging (Kranz et al. J Nucl Med 2014; 55 (Suppl. 1):1143). We performed PET experiments in rhesus monkeys to assess its kinetic and imaging characteristics.

Methods: ¹⁸F-DBT-10 was prepared from its nitrophenyl precursor by nucleophilic substitution. The affinity of DBT-10 on human nAChRs was determined by radioligand binding studies. Dynamic PET imaging of two monkeys (each control and blockade) was performed using a Focus-220 scanner. Brain and plasma metabolites were analysed by HPLC. Regional volumes of distribution (V_T) were estimated from brain and plasma time-activity data.

Results: DBT-10 has high binding affinity to α₇nAChR (K_i = 0.60 nM) and excellent selectivity over other nicotinic receptor subtypes. ¹⁸F-DBT-10 was prepared in 14.5±4.6% radiochemical yield and >99% radiochemical purity (n=5). Free plasma fraction of ¹⁸F-DBT-10 was 18±2 % (n=4). Plasma metabolism varied considerable between the two animals. Brain uptake was high and tissue kinetics fairly fast, with peak uptake at 10-50 min (Figure 1). No radioactive metabolites were found in brain tissue (thalamus, frontal cortex, hippocampus, and cerebellum) taken from one monkey at 120 min p.i. Time-activity curves were fitted well with the 2-tissue kinetic model. Mean V_T values were 58.0, 57.5, 54.9, 54.5, 52.0, 48.4, 39.9, and 34.8 cm³/mL, respectively, for the thalamus, insular, frontal and cingulate cortices, striatum, temporal cortex, hippocampus, occipital cortex, and cerebellum (n=2). Pre-treatment with the selective α₇ ligand ASEM (0.69 & 1.24 mg/kg) dose-dependently reduced binding of ¹⁸F-DBT-10 in all regions by 30% and 64%, respectively.

Conclusions: ¹⁸F-DBT-10 is a novel PET radiotracer with high affinity and selectivity for the α₇nAChR. In rhesus monkeys it displays high uptake, appropriate kinetics and high specific binding in brain and thus is a promising agent for PET imaging of α₇nAChR in humans.

Figure 1. MR and PET VT images (left) and tissue TACs (right) from a baseline scan with 18F-DBT-10.

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