Comparative evaluation of two novel fluorine-18 PET radiotracers for the alpha7 nicotinic acetylcholine receptor (α7nAChR)

Objectives :

The α7nAChR plays an important role in mediating cholinergic transmission, and is considered as biomarker for inflammatory processes and certain types of cancer. [¹⁸F]NS14490 (1), and [¹⁸F]DBT10 (2) showed high in vitro binding affinity and selectivity (K_i,α7= 2.5 and 0.3 nM, K_i,α3β4= 102 and 5000 nM, respectively, and K_i,α3β2both > 800 nM). Here, we report automated radiosyntheses and in vivo PET evaluation in pigs of 1 and 2.

Methods : Syntheses of 1 and 2 were performed in one-step procedure using OTs and NO₂ precursors, respectively, in automated module (Tracerlab FX F-N). Dynamic PET studies (4 h) were performed in anesthetized female juvenile pigs after injection with ~300-400 MBq of 1 or 2 (n=6 each). Blocking studies were performed in 3 pigs each by bolus injection/constant infusion of NS6740 (7 mg/kg), a highly selective α7nAChR ligand. Metabolite-corrected plasma input functions were used for 2-tissue-compartment modeling (2TCM) to determine binding parameters of 1 and 2 in 24 brain regions.

Results : 1 and 2 were synthesized in high radiochemical purities (>92%, >95%), and high specific activities (> 150 GBq/μmol, EOS) with a RCY of 24-36% and 45-50%, respectively. Maximum brain SUVs of 1 (0.54) and 2 (1.89) were reached at 3 and 11.5 min p.i., respectively. Metabolism of 1 and 2 is comparable. At 60 min p.i. about 25% of 1 and 24% of 2 accounted for total radioactivity in plasma. 2TCM of 1 and 2 allowed reliable estimates of k₃ of 1 (-46%) and BP, respectively (Table). NS6740 significantly reduced (* p<0.05) mean k₃ of 1 (-46%) and mean BP of 2 (-75%).

Conclusions : 1 and 2 are promising PET tracers for imaging α7nAChR. Because of higher affinity, brain uptake and specific binding [¹⁸F]DBT10 (2) is selected for further evaluation to obtain approval for translational clinical validation in human beings.

Research Support: DFG (DE 1165/2-1)