title: (99m)Tc(N)-DBODC(5), a potential radiolabeled probe for SPECT of multidrug resistance: in vitro study.
abstract: [(99m)Tc(N)(DBODC)(PNP5)](+) [DBODC is bis(N-ethoxyethyl)dithiocarbamato; PNP5 is bis(dimethoxypropylphosphinoethyl)ethoxyethylamine], abbreviated as (99m)Tc(N)-DBODC(5), is a lipophilic cationic mixed compound investigated as a myocardial imaging agent. The findings that this tracer accumulates in mitochondrial structures through a mechanism mediated by the negative mitochondrial membrane potential and that the rapid efflux of (99m)Tc(N)-DBODC(5) from nontarget tissues seems to be associated with the multidrug resistance (MDR) P-glycoprotein (P-gp) transport function open up the possibility to extend its clinical applications to tumor imaging and noninvasive MDR studies. The rate of uptake at 4 and 37 °C of (99m)Tc(N)-DBODC(5) was evaluated in vitro in selected human cancer cell lines and in the corresponding sublines before and after P-gp and/or MDR-associated protein (MRP) modulator/inhibitor treatment using (99m)Tc-sestamibi as a reference. The results indicated that (1) the uptake of both (99m)Tc(N)-DBODC(5) and (99m)Tc-sestamibi is correlated to metabolic activity of the cells and (2) the cellular accumulation is connected to the level of P-gp/MRP expression; in fact, an enhancement of uptake in resistant cells was observed after treatment with opportune MDR inhibitor/modulator, indicating that the selective blockade of P-gp/MRP prevented efflux of the tracers. This study provides a preliminary indication of the applicability of (99m)Tc(N)-DBODC(5) in tumor imaging and in detecting P-gp/MRP-mediated drug resistance in human cancer. In addition, the possibility to control the hydrophobicity and pharmacological activity of this heterocomplex through the variation of the substituents on the ligands backbone without affecting the P2S2 coordinating sphere makes (99m)Tc(N)-DBODC(5) a suitable scaffold for the preparation of a molecular probe for single photon emission computed tomography of MDR.
authors.affiliation: ICIS-CNR, Corso Stati Uniti 4, 35127 Padua, Italy. bolzati@icis.cnr.it
authors.forename: Cristina
authors.initials: C
authors.lastname: Bolzati
authors.forename: Davide
authors.initials: D
authors.lastname: Carta
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
authors.forename: Nicolò
authors.initials: N
authors.lastname: Morellato
authors.forename: Nicola
authors.initials: N
authors.lastname: Salvarese
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cantore
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D006801:Humans; D015394:Molecular Structure; D017256:Technetium Tc 99m Sestamibi; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017256:Technetium Tc 99m Sestamibi
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