Feasibility and Importance of the alpha 7 Nicotinic Acetylcholine Receptor (alpha 7nAChR) as Target for PET Imaging

Aim:

The α7nAChR is regarded of importance for neurodegeneration, inflammatory processes, certain types of cancer, and in the pathophysiology of atherosclerosis. Our recently developed PET radioligands [¹⁸F]NS14490 and [¹⁸F]DBT-10 showed high in vitro affinity and selectivity towards α7nAChR. We present the automated syntheses and the preclinical evaluation of both radiotracers by PET in pigs and provide evidence on their suitability for imaging of α7nAChRs in the mentioned diseases.
Materials and Methods:
[¹⁸F]NS14490 and [¹⁸F]DBT-10 were synthesized using a Tracerlab FX F-N module by direct radiofluorination using the corresponding tosylate and nitro precursors. Dynamic PET studies (~300-400 MBq) were performed in anaesthetized female piglets under control (n=3 each) and blocking conditions (n=3 each; continuous infusion of the highly selective antagonist ligand NS6740). By compartmental modeling using metabolite-corrected plasma input functions the binding parameters in 24 brain regions and on brain blood vessels were estimated. Parametric maps of the distribution volumes (V_T) of [¹⁸F]NS14490 were calculated. In anticipation of human studies, for [¹⁸F]DBT-10 preclinical dose assessment and toxicity studies were performed.
Results:
[¹⁸F]NS14490 and [¹⁸F]DBT-10 were obtained with comparably high RCY (~30-40%), radiochemical purities (~92-95%) and specific activities (>150 GBq/µmol). Maximum brain uptake was reached at 3 min ([¹⁸F]NS14490 SUV_max:0.54) and 11.5 min p.i. ([¹⁸F]DBT-10 SUV_max:1.89). Comparable metabolism was observed, with 25-30% of both parent compounds in plasma at 60 min p.i. Compartmental modeling allowed reliable estimates of k₃’ and binding potential, BP_ND. NS6740 infusion significantly reduced mean k₃’ of [¹⁸F]NS14490 by 46% and mean BP_ND of [¹⁸F]DBT-10 by 75%. Reduction of V_T on brain blood vessels by NS6740 was clearly visible in parametric maps of [¹⁸F]NS14490. SUV_max in blood vessels of 1.3-1.4 was reached at 2-4 min p.i. NS6740 reduced the SUV by 25-35% at 4 h p.i. The estimated effective dose of [¹⁸F]DBT-10 administration to humans is 12-14 μSv/MBq. DBT-10 toxicity tests did not predict harmfulness for human tracer studies.
Conclusion:
[¹⁸F]NS14490 and [¹⁸F]DBT-10 are promising PET tracers for imaging of α7nAChR. Our preclinical studies provide evidence for the detection of α7nAChRs by PET in the parenchyma and vasculature of pig brain. This further elucidates the feasibility of PET to visualize vascular α7nAChRs, which may present a tool for investigating involvement of α7nAChRs in the pathophysiology of atherosclerosis. [¹⁸F]DBT-10 is selected for further evaluation to obtain approval for translational clinical validation in humans due to its higher affinity, brain uptake, and specific binding.