In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [ 125 I]Iodo-ASEM and [ 18 F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors.

The alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) is involved in several cognitive and physiologic processes; its expression levels and patterns change in neurologic and psychiatric diseases, such as schizophrenia and Alzheimer's disease, which makes it a relevant drug target. Development of selective radioligands is important for defining binding properties and occupancy of novel molecules targeting the receptor. We tested the in vitro binding properties of [I-125]Iodo-ASEM [(3-(1,4-diazabycyclo[3.2.2]nonan-4-yl)-6-(I-125-iododibenzo[b,d]thiopentene 5,5-dioxide)] in the mouse, rat and pig brain using autoradiography. The in vivo binding properties of [F-18]ASEM were investigated using positron emission tomography (PET) in the pig brain. [I-125]Iodo-ASEM showed specific and displaceable high affinity (similar to 1 nM) binding in mouse, rat, and pig brain. Binding pattern overlapped with [I-125]alpha-bungarotoxin, specific binding was absent in alpha 7 nAChR gene-deficient mice and binding was blocked by a range of alpha 7 nAChR orthosteric modulators in an affinity-dependent order in the pig brain. Interestingly, relative to the wild-type, binding in beta 2 nAChR gene-deficient mice was lower for [I-125]Iodo-ASEM (58% +/- 2.7%) than [I-125]alpha-bungarotoxin (23% +/- 0.2%), potentially indicating different binding properties to heteromeric alpha 7 beta 2 nAChR. [F-18]ASEM PET in the pig showed high brain uptake and reversible tracer kinetics with a similar spatial distribution as previously reported for alpha 7 nAChR. Blocking with SSR-180,711 resulted in a significant decrease in [F-18]ASEM binding. Our findings indicate that [I-125]Iodo-ASEM allows sensitive and selective imaging of alpha 7 nAChR in vitro, with better signal-to-noise ratio than previous tracers. Preliminary data of [F-18]ASEM in the pig brain demonstrated principal suitable kinetic properties for in vivo quantification of alpha 7 nAChR, comparable to previously published data.