Synthesis and F-18 labeling of a 2-fluoro dibenzothiophene sulfone derivative, as a potential alpha-7 nicotinic acetylcholine receptor (α7 nAChR) imaging agent

Aim:

The homopentameric α7 nAChR is proposed to be implicated in the pathophysiology of various diseases, e.g. schizophrenia, Alzheimer disease and tumors. Due to a relatively low concentration of α7 subtype binding sites in brain an appropriate PET radiotracer for quantitative molecular imaging requires a sufficiently high receptor affinity. Based upon a novel pharmacophoric lead structure (1) consisting of a diazabicyclononane as amine scaffold, connected to a tricyclic aromatic moiety we developed DBT-10, as potential PET radiotracer for imaging α7 nAChR in brain.

Methods:

DBT-10 was prepared in four steps from 2-nitro-dibenzothiophene in 31% overall yield. Binding affinity for α7 nAChRs was evaluated in vitro by competitive inhibition experiments using H-3 methyllycaconitine. The radiotracer was synthesized by nucleophilic F-18 fluoro-for-nitro aromatic substitution. Animal PET/MR was performed to investigate the radiotracer kinetics in brain.

Results:

A preliminary α7 nAChR affinity of Ki=0.67±0.36 nM (n=4) was determined for DBT-10. For F-18 labeling, 0.5-1.4 mg of NO₂-precursor was converted in the presence of F-18 fluoride, K222/K₂CO₃ in DMF for 10 min at 140°C with 67-87% labeling yield. F-18 DBT-10 was obtained after purification (30% ACN, H₂O, 0.05% TFA, isocratic on Reprosil-Pur AQ 250x10 mm) in 99% RCP and identified by HPLC coinjection of DBT-10. Animal PET/MR revealed fast kinetics of F-18 DBT-10 in mice brain with SUV_max ~1.5 at 3´ p.i.

Conclusions:

The 2-fluoro-dibenzothiophene based DBT-10 was readily prepared and radiolabeled (2). Product F-18 DBT-10 displayed a marked brain uptake in mice and about four-fold higher affinity than our previous α7 nAChR-selective radiotracers suggesting improved suitability for PET imaging.
References:
(1) Schrimpf M. et al. Bioorg. Med. Chem. Lett. 2012, 22, 1633-38; (2) Concurrent to our work a recent paper describes two PET tracers based on the same pharmaceutical lead: Gao et al. J. Med. Chem. 2013, 56, 7574-89.