Adenosine triphosphate-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance-associated proteins (MRPs) are expressed in high concentrations at various physiological barriers (e.g. blood-brain barrier, blood-testis barrier, blood-tumor barrier), where they impede the tissue accumulation of various drugs by active efflux transport. Changes in ABC transporter expression and function are thought to be implicated in various diseases, such as cancer, epilepsy, Alzheimers and Parkinsons disease. The availability of a non-invasive imaging method which allows for measuring ABC transporter function or expression in vivo would be of great clinical use in that it could facilitate the identification of those patients that would benefit from treatment with ABC transporter modulating drugs. To date three different kinds of imaging probes have been described to measure ABC transporters in vivo: i) radiolabelled transporter substrates ii) radiolabelled transporter inhibitors and iii) radiolabelled prodrugs which are enzymatically converted into transporter substrates in the organ of interest (e.g. brain). The design of new imaging probes to visualize efflux transporters is inter alia complicated by the overlapping substrate recognition pattern of different ABC transporter types. The present article will describe currently available ABC transporter radiotracers for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) and critically discuss strengths and limitations of individual probes and their potential clinical applications.

¹¹C-erlotinib is a PET tracer to distinguish responders from nonresponders to epidermal growth factor receptor–targeted tyrosine kinase inhibitors and may also be of interest to predict distribution of erlotinib to tissues targeted for treatment. The aim of this study was to investigate if the known interaction of erlotinib with the multidrug efflux transporters breast cancer resistance protein (humans, ABCG2; rodents, Abcg2) and P-glycoprotein (humans, ABCB1; rodents, Abcb1a/b) affects tissue distribution and excretion of ¹¹C-erlotinib and has an influence on the ability of ¹¹C-erlotinib PET to predict erlotinib tissue distribution at therapeutic doses. Methods: Wild-type and Abcb1a/b or Abcg2 knockout mice underwent ¹¹C-erlotinib PET/MR scans, with or without the coinjection of a pharmacologic dose of erlotinib (10 mg/kg) or after pretreatment with the ABCB1/ABCG2 inhibitor elacridar (10 mg/kg). Integration plot analysis was used to determine organ uptake (CL_uptake) and biliary excretion (CL_bile) clearances of radioactivity. Results: ¹¹C-erlotinib distribution to the brain was restricted by Abcb1a/b and Abcg2, and CL_uptake into the brain was only significantly increased when both Abcb1a/b and Abcg2 were absent (wild-type mice, 0.017 ± 0.004 mL/min/g of tissue; Abcb1a/b^(−/−)Abcg2^(−/−) mice, 0.079 ± 0.013 mL/min/g of tissue; P < 0.001). The pretreatment of wild-type mice with elacridar increased CL_uptake into the brain to levels comparable to Abcb1a/b^(−/−)Abcg2^(−/−) mice (0.090 ± 0.007 mL/min/g of tissue, P < 0.001). The absence of Abcb1a/b and Abcg2 led to a 2.6-fold decrease in CL_bile (wild-type mice, 0.025 ± 0.005 mL/min/g of tissue; Abcb1a/b^(−/−)Abcg2^(−/−) mice, 0.0095 ± 0.001 mL/min/g of tissue; P < 0.001). There were pronounced differences in distribution of ¹¹C-erlotinib to the brain, liver, kidney, and lung and hepatobiliary excretion into intestine between animals injected with a microdose and pharmacologic dose of erlotinib. Conclusion: ABCG2, ABCB1, and possibly other transporters influence in vivo disposition of ¹¹C-erlotinib and thereby affect its distribution to normal and potentially also tumor tissue. Saturable transport of erlotinib leads to nonlinear pharmacokinetics, possibly compromising the prediction of erlotinib tissue distribution at therapeutic doses from PET with a microdose of ¹¹C-erlotinib. The inhibition of ABCB1 and ABCG2 is a promising approach to enhance brain distribution of erlotinib to increase its efficacy in the treatment of brain tumors.

The tyrosine kinase inhibitor erlotinib poorly penetrates the blood-brain barrier (BBB) due to efflux transport by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) thereby limiting its utility in the treatment of non-small cell lung cancer brain metastases. Pharmacological strategies to inhibit ABCB1/ABCG2-mediated efflux transport at the BBB have been successfully developed in rodents, but it remains unclear if these can be translated to humans given pronounced species differences in ABCG2/ABCB1 expression ratios at the BBB. We assessed the efficacy of two different ABCB1/ABCG2 inhibitors to enhance brain distribution of ¹¹C-erlotinib in non-human primates as a model of the human BBB. Methods: Papio anubis baboons underwent PET scans of the brain following i.v. injection of ¹¹C-erlotinib under baseline conditions (n = 4) and during i.v. infusion of high-dose erlotinib (10 mg/kg/h, n = 4) or elacridar (12 mg/kg/h, n = 3). Results: Under baseline conditions, ¹¹C-erlotinib distribution to the brain (total volume of distribution, V_T = 0.22 ± 0.015 mL/cm³) was markedly lower than its distribution to muscle tissue surrounding the skull (V_T = 0.86 ± 0.10 mL/cm³). Elacridar infusion resulted in a 3.5 ± 0.9-fold increase in ¹¹C-erlotinib distribution to the brain (V_T = 0.81 ± 0.21 mL/cm³, P < 0.01), reaching comparable levels as in muscle tissue, without changing ¹¹C-erlotinib plasma pharmacokinetics. During high-dose erlotinib infusion ¹¹C-erlotinib brain distribution was also significantly (1.7 ± 0.2-fold) increased (V_T = 0.38 ± 0.033 mL/cm³, P < 0.05) with a concomitant increase in ¹¹C-erlotinib plasma exposure. Conclusion: We successfully implemented ABCB1/ABCG2 inhibition protocols in non-human primates resulting in pronounced increases in brain distribution of ¹¹C-erlotinib. Such inhibition protocols may ultimately find application for a more effective treatment of patients with brain tumors using drugs that undergo efflux transport at the BBB.