Background: Aripiprazole is a quinolinone derivative. It shows a high affinity for neurotransmitters
dopamine and serotonin receptors, which can overcome the blood-brain barrier (BBB) to reach the central
nervous system (CNS) to exert therapeutic effects. Its radioiodination may lead to high radiochemical yield and
improved its affinity. Aripiprazole radioiodination is an aromatic electrophilic substitution.
Objective: Herein, we investigate the favorable atom site of the aromatic electrophilic substitution of
aripiprazole by calculating the Fukui indices of heavy atoms and ESP charges of the parent molecule.
Methods: The calculations have been carried out at the B3LYP/LanL2DZ level of theory. The iodinated
aripiprazole structure is confirmed by comparing the experimental and the predicted 1H NMR chemical shifts
of the parent molecule and its iodinated forms.
Results: Finally, the electronic properties of aripiprazole and its iodinated form were calculated at the same
level of theory. Nucleophilic Fukui indices and ESP charges calculations confirm that C8 is the most favorable
site of the electrophilic substitution. The calculated electronic properties (e.g, gap energy, electron affinity, and
electronegativity) of aripiprazole and its iodinated form reveal the higher reactivity of iodinated aripiprazole
compared with aripiprazole.
Conclusion: This may explain the higher affinity of iodinated aripiprazole and the increase of its radiochemical