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Up-regulation of CB2R on activated microglial cells, the first step in neurodegeneration, has been widely demonstrated, and this finding makes the receptor a promising target in the early diagnosis and treatment of several neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS). The development of CB2R PET ligands could help demonstrate the neurodegenerative pathogenesis, thus providing useful tools for characterizing the role of neuroinflammation in the progression of these disorders. CB2R agonists and inverse agonists have emerged as neuroprotective agents, and CB2R agonists have entered several clinical trials. CB2R ligands have therefore received great attention, and different molecular scaffolds have been selected to target CB2R subtypes. This review is focused on structure-activity relationship (SAR) and structure-affinity relationship (SAfiR) studies performed on different scaffolds with the aim to identify the molecular features useful for the design of both therapeutic and diagnostic agents.

Starting from our lead compound MC70 displaying high P-glycoprotein (P-gp) inhibition activity but low selectivity, a new class of coumarine derivatives was studied to develop selective and fluorescent P-gp ligands. In this series, the biphenyl moiety of MC70 was replaced with the coumarine fluorophore as a bioisostere of the biphenyl nucleus in order to improve the selectivity toward P-gp and the fluorescent properties for in vitro studies. Moreover, the presence and position of substituents on the coumarine nucleus were probed to develop suitable fluorescent probes to study the expression and activity of P-gp in living cells. The best result was found for compound 4c, which exerts a good P-gp activity profile (EC50 = 13 μM) as substrate and a high selectivity toward the pump since it is inactive toward MRP1.

The development of P-glycoprotein (P-gp) ligands remains of considerable interest, mostly for investigating the protein's structure and transport mechanism. In recent years, many different generations of ligands have been tested for their ability to modulate P-gp activity. The aim of the present work is to perform SAR studies on tetrahydroisoquinoline derivatives in order to design potent and selective P-gp ligands. For this purpose, the effect of bioisosteric replacement and the role of flexibility have been investigated, and four series of tetrahydroisoquinoline ligands have been developed: (a) 2-aryloxazole bioisosteres, (b) elongated analogues, (c) 2H-chromene, and (d) 2-biphenyl derivatives. The results showed that both 2-biphenyl derivative 20b and elongated derivative 6g behaved as strong P-gp substrates. In conclusion, important aspects for developing potent and selective P-gp ligands have been highlighted, providing a solid starting point for further optimization.

In recent years, several PET tracers for monitoring the activity and expression of P-gp at the BBB have been tested. P-gp substrates such as [(11)C]verapamil and [(11)C]loperamide can be employed to visualize P-gp activity, but they display a moderate baseline uptake in the brain and formation of radiolabeled metabolites which hamper the interpretation of PET data. P-gp inhibitors such as [(11)C]elacridar, [(11)C]laniquidar and [(11)C]tariquidar have been tested to investigate P-gp expression and the results need further investigation. Recently, we developed MC18, MC266 and MC80, that have been characterized as an inhibitor, substrate and inducer of P-gp both by in vitro assays and in the everted gut sac method. These compounds have been radiolabelled with (11)C and been evaluated in vivo. In the present review, we compare the outcome of biological in vitro assays and the corresponding in vivo PET data for the P-gp inhibitors [(11)C]MC18 and [(11)C]elacridar, the P-gp substrates [(11)C]MC266 and [(11)C]verapamil, the P-gp inducer [(11)C]MC80 and the P-gp modulator cyclosporin A. Since a satisfactory overlap was found comparing in vivo results and the corresponding in vitro findings, the proposed biological in vitro assays could be predictive for the in vivo PET data of novel radiotracers. PET tracers could be employed for various purposes: radiolabeled P-gp inhibitors to monitor decreased expression of P-gp at the BBB in neurodegenerative disorders such as Alzheimer's and Parkinson's disease; and radiolabeled P-gp substrates with a high baseline uptake to monitor increased expression of P-gp in epileptic foci.

The pharmacological treatment of colorectal tumour leads to MultiDrug Resistance due to overexpression of several ABC transporters such as P-glycoprotein and some Multidrug associated Resistance Proteins (MRPs) that are able to efflux the chemotherapeutic agent out of the cell. A strategy to reverse MDR is the co-administration of antineoplastic agent with a P-glycoprotein inhibitor. These inhibitors are an useful tool for investigating, by PET, the expression and the activity of P-gp and MRPs that are overexpressed in chemoresistant colorectal tumor cells. In this review will be focused the aspect on P-gp and MRPs ligands employed as PET radiotracers considering their pharmacokinetic pharmacodynamic profile and their selectivity towards ABC transporters involved in chemoresistant cell of colorectal tumour.