PET Radiotracers for Imaging P‐glycoprotein: The Challenge for Early Diagnosis in AD

Abstract

PET radiotracer development to target in vivo P-glycoprotein (P-gp) could be an important strategy for the early diagnosis of neurodegenerative disorders such as Alzheimer's disease (AD). Indeed, as a dysfunction of P-gp is responsible for the accumulation of β-amyloid plaques (a hallmark of AD) in brain parenchyma, P-gp is the cause of AD onset. P-gp substrates and inhibitors are useful for imaging the activity or expression of this protein, respectively; herein we discuss the in vivo evaluation of some ¹¹C radiotracers with P-gp-inhibitory activity, such as [¹¹C]MC18 and [¹¹C]MC113, as well as P-gp substrates [¹¹C]MC266 and [¹¹C]MC80. Moreover, the radiosynthesis of all these P-gp probes is reported.

SAR Studies on Tetrahydroisoquinoline Derivatives: The Role of Flexibility and Bioisosterism To Raise Potency and Selectivity toward P-glycoprotein

“…In all of the designed series, the choice of substituents was evaluated for the additional purpose of generating useful tools with easy radiolabeling points, such as a methoxy group or fluorine, for in vivo PET ( 11 C or 18 F) analysis to monitor P-gp activity and expression. − …”

Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics

“…While these aspects above were mostly relevant for therapeutic drug development, the discovery of inhibitors of ABCA7 by addressing the multitarget binding site and their simultaneous derivatization to selective agents would allow for in vivo imaging of ABCA7. Imaging of ABC transporters of the BBB has already been accomplished before [63] , and the results of the present study found the basis for PET tracer development of other, yet under-studied ABC transporters involved in neurological disorders like AD, as for example, ABCA7.…”

“…Additionally, it must be noted that several activators of ABC transporters share molecular-structural features of ABC transporter inhibitors. For example, tetrahydroisoquinolines (ABCB1) [48] , [62] , [63] and pyrrolopyrimidines (ABCC1) [49] , [64] have been described for both activators [48] , [49] and inhibitors [62] , [63] , [64] of ABCB1 and ABCC1, respectively. Other examples are the compound classes of phenothiazines [65] , [66] and purines [49] , [67] , [68] , which have been described to comprise of ABCC1 activators [49] , [65] , [66] and ABCB1 inhibitors [65] , [66] , [67] , [68] .…”

“…Considering these findings, gained knowledge about the multitarget binding site by the use of multitargeting inhibitors may indeed provide necessary molecular-structural information of active scaffolds/substructures for the targeted design of ABCA7 activators (and/or correctors). In addition, imaging techniques using ABC transporter inhibitors have already been demonstrated to trace the expression of the respective ABC transporter in vivo [63] , making ABC transporter inhibitors that are not substrates of the respective ABC transporter ( e.g. , ABCA7) eligible for, e.g.…”

Arylamino Esters As P‐Glycoprotein Modulators: SAR Studies to Establish Requirements for Potency and Selectivity

“…In summary, these results increase our knowledge of the structural determinants for obtaining potent and selective P‐gp substrates or P‐gp inhibitors. These compounds could also be promising candidates as 11 C radiolabeled tracers for in vivo positron emission tomography (PET) imaging, as P‐gp substrates and inhibitors are useful for visualizing P‐gp activity and for the early detection of the in vivo expression of this pump in tumor cells, respectively 30…”