Radiosynthesis and in vivo evaluation of 1-[¹⁸F]fluoroelacridar as a positron emission tomography tracer for P-glycoprotein and breast cancer resistance protein

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• 作者：Bernd D&#xf6 ; rner^a ; ^b ; Claudia Kuntner^c ; Jens P. Bankstahl^d ; Thomas Wanek^c ; Marion Bankstahl^d ; Johann Stanek^b ; Julia Mü ; llauer^c ; Florian Bauer^a ; Severin Mairinger^a ; ^b ; ^c ; Wolfgang L&#xf6 ; scher^d ; Donald W. Miller^e ; Peter Chiba^f ; Markus Mü ; ller^b ; Thomas Erker^a ; ^{thomas.erker@univie.ac.at} ; Oliver Langer^b ; ^c ; ^{oliver.langer@ait.ac.at}
• 关键词：PET ; 1-[¹⁸F]Fluoroelacridar ; P-glycoprotein ; Breast cancer resistance protein ; Blood– ; brain barrier
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：1 April 2011
• 年：2011
• 卷：19
• 期：7
• 页码：2190-2198
• 全文大小：615 K

文摘

Aim of this study was to label the potent dual P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) inhibitor elacridar (1) with ¹⁸F to provide a positron emission tomography (PET) radiotracer to visualize Pgp and BCRP. A series of new 1- and 2-halogen- and nitro-substituted derivatives of 1 (4a–e) was synthesized as precursor molecules and reference compounds for radiolabelling and shown to display comparable in vitro potency to 1 in increasing rhodamine 123 accumulation in a cell line overexpressing human Pgp (MDCKII-MDR1). 1-[¹⁸F]fluoroelacridar ([¹⁸F]4b) was synthesized in a decay-corrected radiochemical yield of 1.7 ± 0.9 % by a 1-step no-carrier added nucleophilic aromatic ¹⁸F-substitution of 1-nitro precursor 4c. Small-animal PET imaging of [¹⁸F]4b was performed in naïve rats, before and after administration of unlabelled 1 (5 mg/kg, n = 3), as well as in wild-type and Mdr1a/b^(−/−)Bcrp1^(−/−) mice (n = 3). In PET experiments in rats, administration of unlabelled 1 increased brain activity uptake by a factor of 9.5 (p = 0.0002, 2-tailed Student’s t-test), whereas blood activity levels remained unchanged. In Mdr1a/b^(−/−)Bcrp1^(−/−) mice, the mean brain-to-blood ratio of activity at 60 min after tracer injection was 7.6 times higher as compared to wild-type animals (p = 0.0002). HPLC analysis of rat brain tissue extracts collected at 40 min after injection of [¹⁸F]4b revealed that 93 ± 7 % of total radioactivity in brain was in the form of unchanged [¹⁸F]4b. In conclusion, the in vivo behavior of [¹⁸F]4b was found to be similar to previously described [¹¹C]1 suggesting transport of [¹⁸F]4b by Pgp and/or BCRP at the rodent BBB. However, low radiochemical yields and a significant degree of in vivo defluorination will limit the utility of [¹⁸F]4b as a PET tracer.