title: 2'[(18)F]-fluoroethylrhodamine B is a promising radiotracer to measure P-glycoprotein function.
abstract: In vivo detection of the emergence of P-glycoprotein (Pgp) mediated multidrug resistance in tumors could be beneficial for patients treated with anticancer drugs. PET technique in combination with appropriate radiotracers could be the most convenient method for detection of Pgp function. Rhodamine derivatives are validated fluorescent probes for measurement of mitochondrial membrane potential and also Pgp function. The aim of this study was to investigate whether 2'[(18)F]-fluoroethylrhodamine B ((18)FRB) a halogenated rhodamine derivative previously synthesized for PET assessment of myocardial perfusion preserved its Pgp substrate character. ATPase assay as well as accumulation experiments carried out using Pgp(+) and Pgp(-) human gynecologic (A2780/A2780(AD) and KB-3-1/KB-V1) and a mouse fibroblast cell pairs (NIH 3T3 and NIH 3T3 MDR1) were applied to study the interaction of (18)FRB with Pgp. ATPase assay proved that (18)FRB is a high affinity substrate of Pgp. Pgp(-) cells accumulated the (18)FRB rapidly in accordance with its lipophilic character. Dissipation of the mitochondrial proton gradient by a proton ionophore CCCP decreased the accumulation of rhodamine 123 (R123) and (18)FRB into Pgp(-) cells. Pgp(+) cells exhibited very low R123 and (18)FRB accumulation (around 1-8% of the Pgp(-) cell lines) which was not sensitive to the mitochondrial proton gradient; rather it was increased by the Pgp inhibitor cyclosporine A (CsA). Based on the above data we conclude that (18)FRB is a high affinity Pgp substrate and consequently a potential PET tracer to detect multidrug resistant tumors as well as the function of physiological barriers expressing Pgp.
authors: Department of Nuclear Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
authors: György
authors: G
authors: Trencsényi
authors: Department of Nuclear Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
authors: István
authors: I
authors: Kertész
authors: Department of Obstetrics and Gynecology, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
authors: Zoárd T
authors: ZT
authors: Krasznai
authors: Department of Nuclear Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
authors: Gábor
authors: G
authors: Máté
authors: Department of Biophysics and Cell Biology, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
authors: Gábor
authors: G
authors: Szalóki
authors: Department of Nuclear Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
authors: P
authors: P
authors: Szabó Judit
authors: Department of Nuclear Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
authors: Levente
authors: L
authors: Kárpáti
authors: Department of Biophysics and Cell Biology, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
authors: Zoltán
authors: Z
authors: Krasznai
authors: Department of Nuclear Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary. Electronic address: marian.terez@med.unideb.hu.
authors: Teréz
authors: T
authors: Márián
authors: Department of Biophysics and Cell Biology, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
authors: Katalin
authors: K
authors: Goda
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D065567:Absorption, Physiological / Q000187:drug effects; D000818:Animals; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D061209:Proton Ionophores / Q000494:pharmacology; D011849:Radioactive Tracers; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism; D012235:Rhodamines / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000378:metabolism*
chemical_list: C546839:2'-fluoroethyl rhodamine B; C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D005456:Fluorescent Dyes; D005462:Fluorine Radioisotopes; D007166:Immunosuppressive Agents; D009363:Neoplasm Proteins; D061209:Proton Ionophores; D011849:Radioactive Tracers; D011994:Recombinant Proteins; D012235:Rhodamines; D020112:Rhodamine 123; D016572:Cyclosporine
keywords: (18)FRB; Calcein-AM (PubChem: CID: 390986); Gynecologic cancer cells; P-glycoprotein; PET; carbonyl cyanide 3-chlorophenylhydrazone (PubChem CID: 2603); cyclosporine A (PubChem CID: 5284373); mitoxanthrone (PubChem CID: 4212); propidium iodide (PubChem CID: 104981); rhodamine 123 (PubChem CID: 65217); rhodamine B (PubChem CID: 6694); tetra fluoroborate (PubChem CID: 28118); verapamil hydrochloride (PubChem CID: 62969)