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The synthesis and characterization of a new series of neutral, six-coordinated mixed-ligand compounds [MIII(PS)2(L)] (M = Re; 99Tc), where PS is bis(arylalkyl)- or trialkylphosphinothiolate and L is dithiocarbamate, are reported. Stable [MIII(PS)2(L)] complexes were easily synthesized, in good yield, starting from precursors where the metal was in different oxidation states (III, V, and VII), involving ligand-exchange and/or redox-substitution reactions. The compounds were characterized by elemental analysis, positive-ion electrospray ionization mass spectrometry, multinuclear NMR spectroscopy, cyclic voltammetry, and X-ray diffraction analysis. All complexes are constituted by the presence of the [MIII(PS)2]+ moiety, where two phosphinothiolate ligands are tightly bound to the metal and the remaining two positions are saturated by a dithiocarbamate chelate, also carrying bulky bioactive molecules [e.g., (2-methoxyphenyl)piperazine]. X-ray analyses were performed on crystalline specimens of four different Re/99Tc compounds sharing a distorted trigonal-prismatic geometry, with a P2S4 coordination donor set. The possibility of easily preparing these [MIII(PS)2(L)] complexes, starting from the corresponding permetalate anions, in mild reaction conditions and in high yield, lays the first stone to the preparation of a new series of MIII-based (M = 99mTc/188Re) compounds potentially useful in theragnostic applications. [ABSTRACT FROM AUTHOR]

A library of homoleptic mononuclear Ga(III) complexes of the general formula [Ga(DTC) 3 ], where DTC is an alicyclic or a linear dithiocarbamate chelator, is reported. The complexes were prepared in high yields starting from Ga(NO 3 ) 3 ·6H 2 O and fully characterized by elemental analysis and IR and NMR spectroscopy. Crystals of five of these complexes were obtained. The antitumor activity of the newly synthesized compounds against a panel of human cancer cell lines was evaluated. The chemical nature of the DTC does not have a marked impact on the structural features of the final compound. X-ray crystal structure analyses revealed that all these complexes have a trigonal prismatic geometry with three identical chelating DTCs coordinating the Ga(III) ion. It is noteworthy that in complex 22, [Ga(NHEt) 3 ] (NHEt = N -ethyldithiocarbamate), the asymmetric unit is formed by two independent and structurally different molecules. Cellular studies showed that all the synthesized Ga-DTC complexes exhibit marked cytotoxic activity, even against human colon cancer cells that are less sensitive to cisplatin. Among the tested compounds, 6 ([Ga(CEPipDTC) 3 ], CEPipDTC = (ethoxycarbonyl)-piperidinedithiocarbamate) and 21 ([Ga(Pr-13) 3 ], PR13 = 4 and N -(2-ethoxy-2-oxoethyl)- N -methyldithiocarbamate) are very promising derivatives, but they have no selectivity towards cancer cells. Nevertheless, the obtained data provide a foundation for developing gallium-dithiocarbamate complexes as anticancer agents.

The purpose of this study was to evaluate the effect of cyclization on the biological profile of a [ 99m Tc(N)(PNP3)]-labeled α-melanocyte stimulating hormone peptide analog. A lactam bridge-cyclized H-Cys-Ahx-βAla 3 -c[Lys 4 -Glu-His-D-Phe-Arg-Trp-Glu 10 ]-Arg 11 -Pro-Val-NH 2 (NAP-NS2) and the corresponding linear H-Cys-Ahx-βAla-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH 2 (NAP-NS1) peptide were synthetized, characterized by ESI-MS spectroscopy and their melanocortin-1 receptor (MC1R) binding affinity was determined in B16/F10 melanoma cells. The consistent [ 99m Tc(N)(PNP3)]-labeled compounds were readily obtained in high specific activity and their stability and biological properties were assessed. As an example, the chemical identity of [ 99m Tc(N)(NAP-NS1)(PNP3)] + was confirmed by carrier added experiments supported by radio/UV HPLC analysis combined with ESI(+)-MS. Compared with the linear peptide, cyclization negatively affected the biological properties of NAP-NS2 peptide by reducing its binding affinity for MC1R and by decreasing the overall excretion rate of the corresponding [ 99m Tc(N)(PNP3)]-labeled peptide from the body as well as its in vivo stability. [ 99m Tc(N)(NAP-NS1)(PNP3)] + was evaluated for its potential as melanoma imaging probe in murine melanoma model. Data from in vitro and in vivo studies on B16/F10 melanoma model of [ 99m Tc(N)(NAP-NS1)(PNP3)] + clearly evidenced that the radiolabeled linear peptide keeps its biological properties up on the conjugation to the [ 99m Tc(N)(PNP3)]-building block. The progressive increase of the tumor-to-nontarget ratios over the time indicates a quite stable interaction between the radio-complex and the MC1R., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A general procedure for the preparation of a new class of neutral six-coordinated mixed ligand [(99m)Tc(III)(PS)2(Ln)] compounds (PS = trisalkyl-phosphino-thiolate; Ln = dithiocarbamate) is reported as well as their in vitro stability and the ex vivo tissue distribution studies. [(99m)Tc(PS)2(Ln)] complexes were prepared in high yield in nearly physiologic conditions following a one-pot procedure. For instance, the chemical identity of [(99m)Tc(PSiso)2(L1)] (PSiso = 2-(diisopropylphosphino)ethanethiol; L1 = pyrrolidine dithiocarbamate) was determined by HPLC comparison with the corresponding (99g)Tc-complex. All complexes comprise the stable [(99m)Tc(III)(PS)2](+) moiety, where the remaining two coordination positions are saturated by a dithiocarbamate chelate, also carrying bioactive molecules (e.g., 2-methoxyphenylpiperazine). [(99m)Tc(PS)2(Ln)] complexes were inert toward ligand exchange reactions. No significant in vitro and in vivo biotransformation were observed, underlining their remarkable thermodynamic stability and kinetic inertness. These results could be conveniently utilized to devise a novel class of (99m)Tc(III)-based compounds useful in radiopharmaceutical applications.

Succinic dihydrazide (SDH), N-methyl-S-methyl dithiocarbazate (HDTCZ) and PEGylated N-methyl-S-methyl dithiocarbazate (HO2C-PEG600-DTCZ) are nitrido nitrogen atom donors employed for the preparation of nitride [M(N)]-complexes (M=(99m)Tc and (188)Re). This study aims to compare the capability and the efficiency of these three N(3-) group donors, in the preparation of [M(N)PNP]-based target-specific compounds (M=(99m)Tc, (188)Re; PNP=aminodiphosphine). For this purpose, three different kit formulations (SDH kit; HO2C-PEG600-DTCZ kit; HDTCZ kit) were assembled and used in the preparation of [M(N)(cys~)(PNP3)](0/+) complexes (cys~=cysteine derivate ligands). For each formulation, the radiochemical yield (RCY) of the [M(N)(~cys)(PNP3)] compounds, was determined by HPLC. The deviation of the percentage of RCY, due to changes in concentration of the N(3-) donors and of the exchanging ligand, was determined. For (99m)Tc, data clearly show that HDTCZ is the most efficient donor of N(3-); however, SDH is the most suitable nitrido nitrogen atom donor for the preparation of [(99m)Tc(N)(PNP)]-based target-specific agents with high specific activity. When HO2C-PEG600-DTCZ or HDTCZ are used in N(3-) donation, high amounts of the exchanging ligand (10(-4)M) were required for the formation of the final complex in acceptable yield. The possibility to use microgram amounts of HDTCZ also in [(188)Re(N)] preparation (0.050mg) reduces its ability to compete in ligand exchange reactions, minimizing the quantity of chelators required to obtain the final complex in high yield. This finding can be exploit for increasing the radiolabeling efficiency in [(188)Re(N)]-radiopharmaceutical preparations compared to the previously reported HDTCZ-based procedure, notwithstanding a purification process could be necessary to improve the specific activity of the complexes., (Copyright © 2014 Elsevier Inc. All rights reserved.)

[(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.