Herein, a series of novel
O
-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities
in vitro
showed that compounds
5a
,
5d
,
5e
,
5f
, and
5h
indicated significantly selective MAO-B inhibitory potency (IC
50
= 0.32, 0.56, 0.54, 0.73, and 0.86 μM, respectively) and moderate antioxidant activity. Moreover, compounds
5a
,
5d
,
5e
,
5f
, and
5h
showed potent anti-inflammatory properties, remarkable effects on self-induced A
β
1-42
aggregation, and potent neuroprotective effect on A
β
1-42
-induced PC12 cell injury. Furthermore, compounds
5a
,
5d
,
5e
,
5f
, and
5h
presented good blood–brain barrier permeation
in vitro
and drug-like properties. More interesting, the PET/CT images with [
11
C]
5f
demonstrated that [
11
C]
5f
could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound
5f
would be a promising multi-functional agent for the treatment of AD.