PET Imaging of Extrathalamic α4β2-nicotinic Acetylcholine Receptors in Health and Disease With [18F]XTRA

Currently, only three radiotracers, (2-\[18F\]FA, 6-\[18F\]FA and \[18F\]AZAN), are available for studying α4β2-nicotinic acetylcholine receptors (α4β2-nAChR) in human brain using PET imaging. A crucial problem for 2-\[18F\] FA, 6-\[18F\] FA and (\[18F\] AZAN is low binding potential (BP) in extrathalamic (ET) regions, including hippocampus, cortex and caudate which have lower receptor densities than the thalamus. The importance of imaging ET-α4β2-nAChRs (ET-nAChR) has emerged from the post-mortem demonstration of altered densities of ET-nAChRs (but not thalamic nAChR) in neurodegenerative diseases and schizophrenia. PET imaging of ET-nAChR may prove to be useful in both detecting early changes and following functional deterioration in neurodegenerative diseases such as Alzheimers disease. Furthermore, PET imaging of ET-nAChR may allow investigation and development of new therapies acting on the acetylcholine system. The imaging drawbacks of the presently available nAChR radioligands have initiated the development of radioligands with greater binding potential by several research groups. The available pre-clinical data on the investigators' new radioligand \[18F\](-)-JHU86428 (\[18F\]XTRA) suggest that this radioligand is superior to 2-\[18F\]FA for quantitative PET imaging of α4β2-nAChR (Gao, J. Med. Chem, 2008). In baboon PET studies \[18F\]XTRA exhibits 200% greater brain uptake, 300% higher BPs and reaches steady-state in approximately 1.5 h in cortical regions post-bolus administration versus 6-8 h for 2-\[18F\]FA. In vitro binding assays shows greater binding affinity of XTRA and similar nAChR-subtype selectivity in comparison with 2-FA. Both ligands bind selectively with the β2-subtypes that are predominant nAChR subtypes in the mammal brain and display little binding affinity at ganglionic α3β4-nAChR. The current planned human protocol will be conducted to (1) determine brain distribution (brain uptake) and test the reproducibility (in test-retest design)