P-Glycoprotein (P-gp) is an efflux transporter widely expressed at the human blood-brain barrier. It is involved in xenobiotics efflux and in onset and progression of neurodegenerative disorders. For these reasons, there is great interest in the assessment of P-gp expression and function by noninvasive techniques such as positron emission tomography (PET). Three radiolabeled aryloxazole derivatives: 2-[2-(2-methyl-(C-11)-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ([C-11]-5); 2-[2-(2-fluoromethyl-(F-18)-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetra-hydroisoquinoline ([F-18]-6); and 2-[2-(2-fluoroethyl-(F-18)-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ([F-18]-7), were tested in several invitro biological assays to assess the effect of the aryl substituent in terms of potency and mechanism of action toward P-gp. Methyl derivative [C-11]-5 is a potent P-gp substrate, whereas the corresponding fluoroethyl derivative [F-18]-7 is a P-gp inhibitor. Fluoromethyl compound [F-18]-6 is classified as a non-transported P-gp substrate, because its efflux increases after cyclosporineA modulation. These studies revealed a promising substrate and inhibitor, [C-11]-5 and [F-18]-7, respectively, for invivo imaging of P-gp by using PET.