PET imaging evaluation of [¹⁸F]DBT-10, a novel radioligand specific to α₇ nicotinic acetylcholine receptors, in nonhuman primates

Purpose Positron emission tomography (PET) radioligands specific to α₇ nicotinic acetylcholine receptors (nAChRs) afford in vivo imaging of this receptor for neuropathologies such as Alzheimer’s disease, schizophrenia, and substance abuse. This work aims to characterize the kinetic properties of an α₇ -nAChR-spe c i f i c radioligand, 7-( 1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-2-[18F]-fluorodibenzo[b,d]thiophene 5,5-dioxide ([¹⁸F]DBT-10), in nonhuman primates.
Methods [¹⁸F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with [¹⁸F]DBT-10 PET, with measurement of [¹⁸F]DBT-10 parent concentrations and metabolism in arterial plasma. Baseline PET scans were acquired for all subjects.
Following one scan, ex vivo analysis of brain tissue was performed to inspect for radiolabeled metabolites in brain. Three blocking scans with 0.69 and 1.24 mg/kg of the α₇-nAChRspecific ligand ASEM were also acquired to assess dosedependent blockade of [¹⁸F]DBT-10 binding. Kinetic analysis of PET data was performed using the metabolite-corrected input function to calculate the parent fraction corrected total distribution volume (V_T/f_P).
Results [¹⁸F]DBT-10 was produced within 90 min at high specific activities of 428±436 GBq/μmol at end of synthesis.
Metabolism of [18F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15–55 %. Uptake of [¹⁸F]DBT-10 in brain occurred rapidly, reaching peak standardized uptake values (SUVs) of 2.9–3.7 within 30 min. The plasma-free fraction was 18.8±3.4 %. No evidence for radiolabeled [¹⁸F]DBT-10 metabolites was found in ex vivo brain tissue samples. Kinetic analysis of PET data was best described by the two-tissue compartment model. Estimated V_T/f_P values were 193–376 ml/cm3 across regions, with regional rank order of thalamus>frontal cortex>striatum>hippocampus>occipital cortex>cerebellum>pons. Dosedependent blockade of [¹⁸F]DBT-10 binding by structural analog ASEMwas observed throughout the brain, and occupancy plots yielded a V_ND/f_P estimate of 20±16 ml/cm³.
Conclusion These results demonstrate suitable kinetic properties of [¹⁸F]DBT-10 for in vivo quantification of α₇-nAChR binding in nonhuman primates.