Abstract
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Objectives: The currently available PET radioligands for imaging nAChR in human brain have substantial drawbacks including slow brain kinetics and low binding potentials. The goal of this study was to design, synthesize and characterize an optimal radioligand for in vivo PET imaging of nAChR.
Methods: A series of nAChR ligands were synthesized by multi-step synthesis. In vitro receptor binding assays of the series were performed using rat cortical membranes and stably expressed cell lines of seven nAChR subtypes. The lipophilicity values (logD7.4) were determined experimentally. [18F]JHU86428, [18F]JHU86430 and [18F]JHU87522 were prepared in one step by radiofluorination of corresponding bromo precursors.
Results: We have synthesized a series of nAChR ligands with picomolar binding affinities at cerebral α4β2-nAChR and low binding affinity at ganglionic α3β4-nAChR. The lipophilicity values of the radioligands were in the optimal range for BBB permeability (logD7.4=0.7-1.0). The best ligands of the series ([18F]JHU86428, [18F]JHU86430 and [18F]JHU87522) were radiolabeled in one step with high radiochemical yields (18-41%), specific activities (6300-43000 mCi/µmol) and radiochemical purity (>98%).
Conclusions: Three high affinity nAChR ligands with optimal logD values for BBB permeability have been synthesized. An automated one-step 18F-radiosynthesis for all radioligands has been developed. The best compound of the series, a selective α4β2-nAChR radioligand [18F]JHU87522, exhibited optimally rapid brain kinetics and high binding potentials (see PET studies in Gao et al., this meeting) and holds great promise for quantitative PET imaging study of nAChRs in humans.
Research Support: JHU Radiology, PDSP/NIMH
- Society of Nuclear Medicine, Inc.