99mTc(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.

Appended Aromatic Moieties in Flexible Bis‐3‐chloropiperidines Confer Tropism against Pancreatic Cancer Cells

“…B‐CePs were recently demonstrated to exploit mechanisms of transporter‐mediated uptake in BxPC‐3 cells [1f] . In order to confirm such mode of entry for the new set of Lys linker derivatives, a modified MTT assay was performed on the highly active compounds 7 , 9 and 10 [1f,10] . As reported in previous works, cells were seeded in two microplates and incubated in parallel at 37 °C or 4 °C for 5 h [1f] .…”

Aromatic Linkers Unleash the Antiproliferative Potential of 3‐Chloropiperidines Against Pancreatic Cancer Cells

“…A modified MTT assay was performed on selected derivatives to investigate their mode of entry in BxPC‐3 cells to disclose possible mechanisms of transporter‐mediated uptake [13] . We analyzed the aromatic B−CePs 1 , 2 , 4 , 6 together with compound 9 as representative of the aliphatic subset.…”

“…The method was validated in this modified version using cisplatin as positive internal control (Figure S2). This drug is known to exploit transporters to enter cells [13,19] …”

Nitrido Technetium-99 m Core in Radiopharmaceutical Applications: Four Decades of Research

“…Mechanistic studies of some of these [ 99m Tc][TcN(L)(PNP)] + complexes established that their favorable pharmacokinetic profile is due to the combined action of two main biochemical processes [103,105,113,114]. The first one is the myocardial uptake, as a result of the build-up of these monocationic agents into mitochondrial structures of myocytes (where they are particularly abundant: 40% of the total volume of myocytes is occupied by mitochondria), in response to the negative mitochondrial membrane potential.…”