The novel fluorine-18 PET radiotracer [¹⁸F]NS14490 allows in vivo investigation of alpha7 nicotinic acetylcholine receptor (α7-nAChR) expression on brain vasculature

Objectives :

The α7nAChR plays an important role in the pathophysiology of atherosclerosis, where it is known to mediate the deleterious effects of nicotine. Recently, [¹⁸F]NS14490 was described as radioligand with high in vitro binding affinity and selectivity towards α7nAChR (K_i, α7=2.5), K_i, α3β4=102, K_i, α4β2>800 nM) [BMC 21(2013), 2635]. Here, we report in vivo investigation of α7nAChR in brain blood vessels of pigs using [F]NS14490 and PET.

Methods : The synthesis of [¹⁸F]NS14490 and pig studies were performed as reported [Teodoro et al. this volume]. Baseline (n=3) and blocking studies with NS6740 (n=3) were done. Volumes of interest for the left carotid artery (LCA) and Circle of Willis (CW) were drawn with reference to T1-weighed MR images aligned to a summed PET image. Metabolite-corrected plasma input functions were used for 2-tissue-compartment (2TC) modelling to determine receptor parameters. Parametric maps of the distribution volumes (VT) were calculated for baseline and blocking conditions.

Results : Reduction of VT on brain vasculature was clearly visible in parametric maps of [¹⁸F]NS14490.
Maximum SUV in LCA (1.4±0.2) and CW (1.3±0.2) was reached at 4 and 2 min p.i., respectively. At 4 h after blockade, the SUV in LCA was reduced by 36%, with lesser declines in CW. Using an 2TC irreversible binding model, we found a [¹⁸F]NS14490 k₃ of 0.0023 min-1 in LCA, which was 40% blocked by NS6740.

Conclusions :

The study provides first evidence for the detection of α7nAChRs by PET in the pig brain vasculature, notably in the LCA. This further elucidates the feasibility of PET to non-invasively image vascular image vascular α7nAChRs.

Research Support: Support from DFG (DE 1165/2-1, Dan Peters (DanPET AB) and Matthias Scheunemann is gratefully acknowledged.
References: 1.Rötering S., Scheunemann M., Fischer S. et al. (2013) Radiosynthesis and first evaluation in mice of [(18)F]NS14490 for molecular imaging of α7 nicotinic acetylcholine receptors. Bioorg Med Chem 21, 2635
2. Teodoro R, Deuther-Conrad W, Rötering S, et al. (2013) Comparative evaluation of two novel fluorine-18 PET radiotracers for the alpha7 nicotinic acetylcholine receptor (α7nAChR), submitted