The cannabinoid receptor type 2 (CB2R) is an attractive target for diagnosis and therapy of neurodegenerative diseases and cancer. Recently, we reported a novel naphthyrid-2-one based positron-emission tomography (PET) radioligand for imaging of the CB2R in the brain ([18F]5). In this study we aimed at the development of a novel 18F-labeled CB2R radioligand with improved binding properties and metabolic stability. Starting from the structure of 5, we developed a novel series of fluorinated derivatives by modifying the substituents at the naphthyrid-2-one subunit. Compound 28 (LU13) was identified with the highest binding affinity and selectivity versus CB1R (CB2RKi = 0.6 nM; CB1RKi/CB2RKi > 1000) and was selected for radiolabeling with 18F and biological characterization. The radiofluorination was performed starting from the corresponding bromo-precursor (31) bearing a fully deuterated N-alkyl chain to protect against defluorination. The in vitro evaluation of [18F]LU13 proved the high binding affinity of the radioligand towards rat (rCB2RKD = 0.2 nM) and human (hCB2RKD = 1.1 nM) CB2R. Metabolism studies in mice revealed a metabolic stability at 30 min p.i. with fractions of parent compound of >80% in the brain and 90% in the spleen with only trace of defluorination products detected in plasma. PET imaging in a rat model of vector-based/related overexpression in the striatum revealed a high signal to background ratio, demonstrating the ability of [18F]LU13 to reach and selectively label the hCB2R in the brain. Thus, [18F]LU13 is a novel and highly promising PET radioligand for the imaging of up regulated CB2R expression under pathological conditions in the brain.