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

Abstract

Purpose 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 specific 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-nAChR-specific ligand ASEM were also acquired to assess dose-dependent 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 (VT/fP). 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 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 VT/fP values were 193–376 mL/cm3 across regions, with regional rank order of thalamus > frontal cortex > striatum > hippocampus > occipital cortex > cerebellum > pons. Dose dependent blockade of [18F]DBT-10 binding by structural analog ASEM was observed throughout the brain, and occupancy plots yielded a VND/fP estimate of 20±16 mL/cm3. Conclusions These results demonstrate suitable kinetic properties of [18F]DBT-10 for in vivo quantification of α7-nAChR binding in nonhuman primates.

PET imaging of α7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans

“…Production of both [ 18 F]ASEM and [ 18 F]DBT-10 was performed as previously described 14 . Briefly, both radiotracers were prepared via radiofluorination of their corresponding nitro precursors in the presence of Kryptofix-222.…”

“…List-mode PET data were continuously acquired for up to 240 min. Discrete arterial blood samples were manually acquired and analyzed to measure the parent input function as described in Supplement B, consistent with previous procedures 14 . Additionally, the free fraction ( f P ) in plasma was measured with ultrafiltration cartridges (Millipore Centifree UF devices) in triplicate for each scan.…”

“…Additionally, the free fraction ( f P ) in plasma was measured with ultrafiltration cartridges (Millipore Centifree UF devices) in triplicate for each scan. The baseline [ 18 F]DBT-10 scans were previously reported 14 .…”

“…The second session lasted from 150 min to 180 min post-injection, with a second 137 Cs transmission scan acquired afterwards. Blood samples were manually acquired from a radial artery to measure the metabolite-corrected arterial input function and analyzed using the same methods as in nonhuman primate experiments described above 14 and in Supplement B.…”

“…Subsequent evaluation under different in vitro binding conditions reported that [ 18 F]DBT-10 had higher affinity and selectivity than [ 18 F]ASEM for α 7 nAChRs with similar feasibility for radiofluorination at this position (see Supplement A), thus motivating its preclinical evaluation in PET imaging studies 13 . [ 18 F]DBT-10 was found to have high uptake and binding potentials in nonhuman primates with suitable kinetic properties for in vivo quantification of α 7 nAChR availability 14 .…”