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 (BPND), 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 (BPND = 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.