Imaging α4β2 Nicotinic Acetylcholine Receptors (nAChRs) in Baboons with [¹⁸F]XTRA, a Radioligand with Improved Specific Binding in Extra-Thalamic Regions

Purpose: Currently available positron-emitting radiotracers for imaging of the α4β2 subtype of nicotinic acetylcholine receptors (nAChRs) exhibit high and moderate specific binding in the thalamus and extra-thalamic brain regions, respectively. In many neuropsychiatric disorders, α4β2-nAChRs are altered in the extra-thalamic brain regions, but not necessarily in the thalamus. The purpose of this study was to evaluate [¹⁸F]XTRA, a new α4β2-nAChR positron emission tomography (PET) radioligand with improved specific binding in extra-thalamic brain regions, in non-human primates. Procedures: The regional distribution of [¹⁸F]XTRA in the brain of Papio anubis baboons was evaluated in baseline and blocking experiments. Various PET modeling procedures were used for determination of volume of distribution (V_T), binding potential (BP_ND), and receptor occupancy. Radiation dosimetry for [¹⁸F]XTRA was studied in male CD-1 mice and extrapolated to human dosimetry estimates using OLINDA/EXM software. Results: [¹⁸F]XTRA was synthesized using an automated radiochemistry module with 25 % decay-corrected radiochemical yield. [¹⁸F]XTRA readily enters the baboon brain and specifically labels α4β2-nAChRs. Mathematical modeling demonstrates high binding potential values (BP_ND = 7 and 1.3 in the thalamus and frontal cortex, respectively). A PET scanning time of 90–120 min was sufficient to obtain stable V_T values in the extra-thalamic regions. The extrapolated human effective dose was 0.041 mSv/MBq (0.15 Rem/mCi). Conclusion: [¹⁸F]XTRA exhibits improved specific binding in the baboon brain including extra-thalamic regions and it is considered radiologically acceptable for human studies. Further evaluations of [¹⁸F]XTRA in human subjects are under way.