Recently, the azepino[4,3-b]indole-1-one derivative 1 showed in vitro nanomolar inhibition against butyrylcholinesterase (BChE), the ChE isoform that plays a role in the progression and pathophysiology of Alzheimer's disease (AD), and protects against N-methyl- d-aspartate-induced neuronal toxicity. Three 9-R-substituted (R = F, Br, OMe) congeners were investigated. The 9-F derivative (2a) was found more potent as BChE inhibitors (half-maximal inhibitory concentration value = 21 nM) than 2b (9-Br) and 2c (9-OMe), achieving a residence time (38 s), assessed by surface plasmon resonance, threefold higher than that of 1. To progress in featuring the in vivo pharmacological characterization of 2a, herein the 18F-labeled congener 2a was synthesized, by applying the aromatic 18F-fluorination method, and its whole-body distribution in healthy mice, including brain penetration, was evaluated through positron emission tomography imaging. [18F]2a exhibited a rapid and high brain uptake (3.35 ± 0.26% ID g−1 at 0.95 ± 0.15 min after injection), followed by a rapid clearance (t1/2 = 6.50 ± 0.93 min), showing good blood–brain barrier crossing. After a transient liver accumulation of [18F]2a, the intestinal and urinary excretion was quantified. Finally, ex vivo pharmacological experiments in mice showed that the unlabeled 2a affects the transmitters' neurochemistry, which might be favorable to reverse cognition impairment in mild-to-moderate AD-related dementias.
Radiosynthesis and whole-body distribution in mice of a 18F-labeled azepino[4,3-b]indole-1-one derivative with multimodal activity for the treatment of Alzheimer's disease
Morgese M. G.;Tucci P.;Trabace L.;
2023-01-01
Abstract
Recently, the azepino[4,3-b]indole-1-one derivative 1 showed in vitro nanomolar inhibition against butyrylcholinesterase (BChE), the ChE isoform that plays a role in the progression and pathophysiology of Alzheimer's disease (AD), and protects against N-methyl- d-aspartate-induced neuronal toxicity. Three 9-R-substituted (R = F, Br, OMe) congeners were investigated. The 9-F derivative (2a) was found more potent as BChE inhibitors (half-maximal inhibitory concentration value = 21 nM) than 2b (9-Br) and 2c (9-OMe), achieving a residence time (38 s), assessed by surface plasmon resonance, threefold higher than that of 1. To progress in featuring the in vivo pharmacological characterization of 2a, herein the 18F-labeled congener 2a was synthesized, by applying the aromatic 18F-fluorination method, and its whole-body distribution in healthy mice, including brain penetration, was evaluated through positron emission tomography imaging. [18F]2a exhibited a rapid and high brain uptake (3.35 ± 0.26% ID g−1 at 0.95 ± 0.15 min after injection), followed by a rapid clearance (t1/2 = 6.50 ± 0.93 min), showing good blood–brain barrier crossing. After a transient liver accumulation of [18F]2a, the intestinal and urinary excretion was quantified. Finally, ex vivo pharmacological experiments in mice showed that the unlabeled 2a affects the transmitters' neurochemistry, which might be favorable to reverse cognition impairment in mild-to-moderate AD-related dementias.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
