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Theranostic radioisotope pairs such as Gallium-68 ( 68 Ga) for Positron Emission Tomography (PET) and Lutetium-177 ( 177 Lu) for radioisotopic therapy, in conjunction with nanoparticles (NPs), are an emerging field in the treatment of cancer. The present work aims to demonstrate the ability of condensed colloidal nanocrystal clusters (co-CNCs) comprised of iron oxide nanoparticles, coated with alginic acid (MA) and stabilized by a layer of polyethylene glycol (MAPEG) to be directly radiolabeled with 68 Ga and its therapeutic analog 177 Lu. 68 Ga/ 177 Lu- MA and MAPEG were investigated for their in vitro stability. The biocompatibility of the non-radiolabeled nanoparticles, as well as the cytotoxicity of MA, MAPEG, and [ 177 Lu]Lu-MAPEG were assessed on 4T1 cells. Finally, the ex vivo biodistribution of the 68 Ga-labeled NPs as well as [ 177 Lu]Lu-MAPEG was investigated in normal mice. Radiolabeling with both radioisotopes took place via a simple and direct labelling method without further purification. Hemocompatibility was verified for both NPs, while MTT studies demonstrated the non-cytotoxic profile of the nanocarriers and the dose-dependent toxicity for [ 177 Lu]Lu-MAPEG. The radiolabeled nanoparticles mainly accumulated in RES organs. Based on our preliminary results, we conclude that MAPEG could be further investigated as a theranostic agent for PET diagnosis and therapy of cancer.

Radiolabeled gold nanoparticles (AuNPs) have been widely used for cancer diagnosis and therapy over recent decades. In this study, we focused on the development and in vitro evaluation of four new Au nanoconjugates radiolabeled with technetium-99m ( 99m Tc) via thiol-bearing ligands attached to the NP surface. More specifically, AuNPs of two different sizes (2 nm and 20 nm, referred to as Au (2) and Au (20) , respectively) were functionalized with two bifunctional thiol ligands (referred to as L 1 H and L 2 H). The shape, size, and morphology of both bare and ligand-bearing AuNPs were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) techniques. In vitro cytotoxicity was assessed in 4T1 murine mammary cancer cells. The AuNPs were successfully radiolabeled with 99m Tc-carbonyls at high radiochemical purity (>95%) and showed excellent in vitro stability in competition studies with cysteine and histidine. Moreover, lipophilicity studies were performed in order to determine the lipophilicity of the radiolabeled conjugates, while a hemolysis assay was performed to investigate the biocompatibility of the bare and functionalized AuNPs. We have shown that the functionalized AuNPs developed in this study lead to stable radiolabeled nanoconstructs with the potential to be applied in multimodality imaging or for in vivo tracking of drug-carrying AuNPs.

The aim of this study was to develop a bioimaging probe based on magnetic iron oxide nanoparticles (MIONs) surface functionalized with the copolymer (p(MAA-g-EGMA)), which were radiolabeled with the positron emitter Gallium-68. The synthesis of the hybrid MIONs was realized by hydrolytic condensation of a single ferrous precursor in the presence of the copolymer. The synthesized MagP MIONs displayed an average D h of 87 nm, suitable for passive targeting of cancerous tissues through the enhanced permeation and retention (EPR) effect after intravenous administration, while their particularly high magnetic content ascribes strong magnetic properties to the colloids. Two different approaches were explored to develop MIONs radiolabeled with 68 Ga: the chelator-mediated approach, where the chelating agent NODAGA-NHS was conjugated onto the MIONs (MagP-NODAGA) to form a chelate complex with 68 Ga, and the chelator-free approach, where 68 Ga was directly incorporated onto the MIONs (MagP). Both groups of NPs showed highly efficient radiolabeling with 68 Ga, forming constructs which were stable with time, and in the presence of PBS and human serum. Ex vivo biodistribution studies of [ 68 Ga]Ga- MIONs showed high accumulation in the mononuclear phagocyte system (MPS) organs and satisfactory blood retention with time. In vivo PET imaging with [ 68 Ga]Ga-MagP MIONs was in accordance with the ex vivo biodistribution results. Finally, the MIONs showed low toxicity against 4T1 breast cancer cells. These detailed studies established that [ 68 Ga]Ga- MIONs exhibit potential for application as tracers for early cancer detection.

Purpose: To evaluate the antitumor efficacy of Ag 3 Au 1 Trp 1:2 NPs in a SCID mouse cancer model, with respect to their effect on tumor growth, on tumor's metastatic potential and the underlying molecular mechanism., Subjects and Methods: Ag 3 Au 1 Trp 1:2 NPs were radiolabeled with Gallium-68 and the biodistribution was studied in Swiss mice without tumors and in SCID mice bearing tumors. SCID mice received intratumoral Ag 3 Au 1 Trp 1:2 NPs and tumor size was measured using calipers. Lung and liver tissues were extracted and studied microscopically for the detection of any metastatic sites. Changes in the Caspase-3 and TNF-related apoptosis-inducing ligand (TRAIL) were also investigated using real-time PCR and Western blot techniques, respectively., Results: In the 4T1 tumor-bearing SCID mice, Ag 3 Au 1 Trp 1:2 NPs showed quick passive accumulation at tumor sites at 30 mins post-injection. Mice that received the highest dose of NPs (5.6mg/mL) demonstrated a 1.9-fold lower tumor volume compared to that of the control group at 11 days post-injection, while mice that did not receive NPs showed metastatic sites in liver and lung. Extracted tumor tissue of treated mice revealed increased Casp-3 mRNA levels as well as elevated TRAIL protein levels., Conclusion: Based on our results, Ag 3 Au 1 Trp 1:2 NPs express anti-tumor and anti-metastatic effects in vivo. Ag 3 Au 1 Trp 1:2 NPs also reach tumor site via the enhancement and retention effect which results in the apoptotic death of cancerous cells selectively via the extrinsic TRAIL-dependent pathway., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Katifelis et al.)

Actinium-225 ( 225 Ac) is receiving increased attention for its application in targeted radionuclide therapy, due to the short range of its emitted alpha particles in conjunction with their high linear energy transfer, which lead to the eradication of tumor cells while sparing neighboring healthy tissue. The objective of our study was the evaluation of a gold nanoparticle radiolabeled with 225 Ac as an injectable radiopharmaceutical form of brachytherapy for local radiation treatment of cancer. Au@TADOTAGA was radiolabeled with 225 Ac at pH 5.6 (30 min at 70 °C), and in vitro stability was evaluated. In vitro cytotoxicity was assessed in U-87 MG cancer cells, and in vivo biodistribution was performed by intravenous and intratumoral administration of [ 225 Ac] 225 Ac-Au@TADOTAGA in U-87 MG tumor-bearing mice. A preliminary study to assess therapeutic efficacy of the intratumorally-injected radio-nanomedicine was performed over a period of 22 days, while the necrotic effect on tumors was evaluated by a histopathology study. We have shown that [ 225 Ac] 225 Ac-Au@TADOTAGA resulted in the retardation of tumor growth after its intratumoral injection in U87MG tumor-bearing mice, even though very low activities were injected per mouse. This gold nanoparticle radiopharmaceutical could be applied as an unconventional brachytherapy in injectable form for local radiation treatment of cancer.

Purpose: The aim of this study was to demonstrate the potential of Ga-68-labeled macrocycle (DOTA-en-pba) conjugated with phenylboronic vector for tumor recognition by positron emission tomography (PET), based on targeting of the overexpressed sialic acid (Sia)., Procedures: The imaging reporter DOTA-en-pba was synthesized and labeled with Ga-68 at high efficiency. Cell binding assay on Mel-C and B16-F10 melanoma cells was used to evaluate melanin production and Sia overexpression to determine the best model for demonstrating the capability of [ 68 Ga]DOTA-en-pba to recognize tumors. The in vivo PET imaging was done with B16-F10 tumor-bearing SCID mice injected with [ 68 Ga]DOTA-en-pba intravenously. Tumor, blood, and urine metabolites were assessed to evaluate the presence of a targeting agent., Results: The affinity of [ 68 Ga]DOTA-en-pba to Sia was demonstrated on B16-F10 melanoma cells, after the production of melanin as well as Sia overexpression was proved to be up to four times higher in this cell line compared to that in Mel-C cells. Biodistribution studies in B16-F10 tumor-bearing SCID mice showed blood clearance at the time points studied, while uptake in the tumor peaked at 60 min post-injection (6.36 ± 2.41 % ID/g). The acquired PET images were in accordance with the ex vivo biodistribution results. Metabolite assessment on tumor, blood, and urine samples showed that [ 68 Ga]DOTA-en-pba remains unmetabolized up to at least 60 min post-injection., Conclusions: Our work is the first attempt for in vivo imaging of cancer by targeting overexpression of sialic acid on cancer cells with a radiotracer in PET.

Superparamagnetic iron oxide nanoparticles with well-integrated multimodality imaging properties have generated increasing research interest in the past decade, especially when it comes to the targeted imaging of tumors. Bevacizumab (BCZM) on the other hand is a well-known and widely applied monoclonal antibody recognizing VEGF-A, which is overexpressed in angiogenesis. The aim of this proof-of-concept study was to develop a dual-modality nanoplatform for in vivo targeted single photon computed emission tomography (SPECT) and magnetic resonance imaging (MRI) of tumor vascularization. Iron oxide nanoparticles (IONPs) have been coated with dimercaptosuccinic acid (DMSA), for consequent functionalization with the monoclonal antibody BCZM radiolabeled with 99m Tc, via well-developed surface engineering. The IONPs were characterized based on their size distribution, hydrodynamic diameter and magnetic properties. In vitro cytotoxicity studies showed that our nanoconstruct does not cause toxic effects in normal and cancer cells. Fe 3 O 4 -DMSA-SMCC-BCZM- 99m Tc were successfully prepared at high radiochemical purity (>92%) and their stability in human serum and in PBS were demonstrated. In vitro cell binding studies showed the ability of the Fe 3 O 4 -DMSA-SMCC-BCZM- 99m Tc to bind to the VEGF-165 isoform overexpressed on M-165 tumor cells. The ex vivo biodistribution studies in M165 tumor-bearing SCID mice showed high uptake in liver, spleen, kidney and lungs. The Fe 3 O 4 -DMSA-SMCC-BCZM- 99m Tc demonstrated quick tumor accumulation starting at 8.9 ± 1.88%ID/g at 2 h p.i., slightly increasing at 4 h p.i. (16.21 ± 2.56%ID/g) and then decreasing at 24 h p.i. (6.01 ± 1.69%ID/g). The tumor-to-blood ratio reached a maximum at 24 h p.i. (~7), which is also the case for the tumor-to-muscle ratio (~18). Initial pilot imaging studies on an experimental gamma-camera and a clinical MR camera prove our hypothesis and demonstrate the potential of Fe 3 O 4 -DMSA-SMCC-BCZM- 99m Tc for targeted dual-modality imaging. Our findings indicate that Fe 3 O 4 -DMSA-SMCC-BCZM- 99m Tc IONPs could serve as an important diagnostic tool for biomedical imaging as well as a promising candidate for future theranostic applications in cancer.

The aim of this study was to develop a dual-modality PET/MR imaging probe by radiolabeling iron oxide magnetic nanoparticles (IONPs), surface functionalized with water soluble stabilizer 2,3-dicarboxypropane-1,1-diphosphonic acid (DPD), with the positron emitter Gallium-68. Magnetite nanoparticles (Fe 3 O 4 MNPs) were synthesized via coprecipitation method and were stabilized with DPD. The Fe 3 O 4 -DPD MNPs were characterized based on their structure, morphology, size, surface charge, and magnetic properties. In vitro cytotoxicity studies showed reduced toxicity in normal cells, compared to cancer cells. Fe 3 O 4 -DPD MNPs were successfully labeled with Gallium-68 at high radiochemical purity (>91%) and their stability in human serum and in PBS was demonstrated, along with their further characterization on size and magnetic properties. The ex vivo biodistribution studies in normal Swiss mice showed high uptake in the liver followed by spleen. The acquired PET images were in accordance with the ex vivo biodistribution results. Our findings indicate that 68 Ga-Fe 3 O 4 -DPD MNPs could serve as an important diagnostic tool for biomedical imaging.

Aim: The aim of this study was to develop a dual-modality positron emission tomography/magnetic resonance (PET/MR) imaging probe by radiolabeling gadolinium-containing AGuIX derivatives with the positron-emitter Gallium-68 ( 68 Ga)., Materials & Methods: AGuIX@NODAGA nanoparticles were labeled with 68 Ga at high efficiency. Tumor accumulation in an appropriate disease model was assessed by ex vivo biodistribution and in vivo PET/MR imaging., Results:   68 Ga-AGuIX@NODAGA was proven to passively accumulate in U87MG human glioblastoma tumor xenografts. Metabolite assessment in serum, urine and tumor samples showed that 68 Ga-AGuIX@NODAGA remains unmetabolized up to at least 60 min postinjection., Conclusion: This study demonstrates that 68 Ga-AGuIX@NODAGA can be used as a dual-modality PET/MR imaging agent with passive accumulation in the diseased area, thus showing great potential for PET/MR image-guided radiation therapy.

Nanoparticles made of a polysiloxane matrix and surrounded by 1,4,7,10-tetraazacyclododecane-1-glutaric anhydride-4,7,10-triacetic acid (DOTAGA)[Gd(3+) ] and 2,2'-(7-(1-carboxy-4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid) NODAGA[(68) Ga(3+) ] have been synthesized for positron emission tomography/magnetic resonance (PET/MRI) dual imaging. Characterizations were carried out in order to determine the nature of the ligands available for radiolabelling and to quantify them. High radiolabelling purity (>95%) after (68) Ga labelling was obtained. The MR and PET images demonstrate the possibility of using the nanoparticles for a combined PET/MR imaging scanner. The images show fast renal elimination of the nanoparticles after intravenous injection., (Copyright © 2014 John Wiley & Sons, Ltd.)

The synthesis and characterization of neutral mixed ligand complexes fac-[M(CO)3(P)(OO)] and cis-trans-[M(CO)2(P)2(OO)] (M = Re, (99m)Tc), with deprotonated acetylacetone or curcumin as the OO donor bidentate ligands and a phosphine (triphenylphosphine or methyldiphenylphosphine) as the monodentate P ligand, is described. The complexes were synthesized through the corresponding fac-[M(CO)3(H2O)(OO)] (M = Re, (99m)Tc) intermediate aqua complex. In the presence of phosphine, replacement of the H2O molecule of the intermediate complex at room temperature generates the neutral tricarbonyl monophosphine fac-[Re(CO)3(P)(OO)] complex, while under reflux conditions further replacement of the trans to the phosphine carbonyl generates the new stable dicarbonyl bisphosphine complex cis-trans-[Re(CO)2(P)2(OO)]. The Re complexes were fully characterized by elemental analysis, spectroscopic methods, and X-ray crystallography showing a distorted octahedral geometry around Re. Both the monophosphine and the bisphosphine complexes of curcumin show selective binding to β-amyloid plaques of Alzheimer's disease. At the (99m)Tc tracer level, the same type of complexes, fac-[(99m)Tc(CO)3(P)(OO)] and cis-trans-[(99m)Tc(CO)2(P)2(OO)], are formed introducing new donor combinations for (99m)Tc(I). Overall, β-diketonate and phosphine constitute a versatile ligand combination for Re(I) and (99m)Tc(I), and the successful employment of the multipotent curcumin as β-diketone provides a solid example of the pharmacological potential of this system.

The synthesis, characterization and biological evaluation of two new neutral tricarbonyl fac-M(CO)(3)(SNO) (M=Re, (99m)Tc) bearing o-methoxyphenylpiperazine as pharmacophore and S-functionalized cysteine or penicillamine as chelators are reported. Competition binding tests showed good affinity for the 5-HT(1A) receptor (8 and 54 nM for 4a and 4b, respectively). Biodistribution studies in healthy animals showed high initial blood and liver uptake, fast blood and tissue depuration and negligible brain uptake., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Dual-modality contrast agents, such as radiolabeled nanoparticles, are promising candidates for a number of diagnostic applications, since they combine the advantages of two different imaging modalities, namely SPECT or PET imaging with MR imaging. The benefit of such a combination is to more accurately interpret disease and abnormalities in vivo, by exploiting the advantages of each imaging technique, i.e. high sensitivity for SPECT/PET, high resolution anatomical information for MRI. In this review article, we provide an overview of recent findings in the synthesis, evaluation and application of radiolabeled iron oxide nanoparticles as dual-modality SPECT/MRI and PET/MRI imaging probes.

The synthesis and characterization of three neutral tricarbonyl fac-M(CO)3(NNO) (M = Re, (99m)Tc) complexes based on the picolylamine N,N-diacetic acid (PADA) ligand is reported. One of the two carboxylate groups of the PADA ligand is efficiently and conveniently derivatized with an amine nucleophile through the use of the PADA anhydride. In this work, aniline, benzylamine and pyrrolidine were used as model amine nucleophiles. The rhenium complexes were synthesized using the [NEt4]2[Re(CO)3Br3] precursor and fully characterized by elemental analysis, spectroscopic methods, and X-ray crystallography. The analogous technetium-99m complexes were also prepared quantitatively using the [(99m)Tc(CO)3(H2O)3](+) precursor. The reaction scheme presented for the synthesis of the fac-M(CO)3(NNO) (M = Re, (99m)Tc) complexes can be applied to the development of target-specific radiopharmaceuticals because, in principle, any bioactive pharmacophore bearing an amine group can be used in the place of the model amine nucleophiles.

The present paper deals with the synthesis and structural characterization of novel neutral oxorhenium(V) complexes of the general formula ReO[SNO][NN]. The simultaneous action of the tridentate SNO ligand, N-(2-mercaptoacetyl)glycine (1), and the bidentate NN ligand, N-phenylpyridine-2-aldimine (2), on ReOCl3(PPh3)2 leads to the formation of two isomers 4a and 4b of the general formula ReO[SNO][NN], as a result of the different orientations of the NN ligand. In both cases, the SNO donor atoms of the tridentate ligand occupy the three positions in the equatorial plane of the distorted octahedron, whereas the oxo group is always directed toward one of the apical positions. In the first isomer, 4a, the imino nitrogen of the NN ligand occupies the fourth equatorial position and the pyridine type nitrogen is directed trans to the oxo group, while in the second isomer, 4b, the imino nitrogen of the NN ligand occupies the apical position trans to the oxo group and the pyridine type nitrogen completes the equatorial plane of the distorted octahedron. The [SNO][NN] mixed-ligand system was applied in the synthesis of the oxorhenium complex 5 in which the 1-(2-methoxyphenyl)piperazine moiety, a fragment of the true 5-HT1A antagonist WAY 100635, has been incorporated in the NN bidentate ligand (NN is N-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}pyridine-2-aldimine). In this case, high-performance liquid chromatography and NMR showed the existence of one isomer, 5, in which the pyridine nitrogen is trans to the oxo core, as demonstrated by crystal structure analysis.

The present paper investigates the conditional volatility properties of apneic electrocardiogram (ECG) sequences taken from the Physionet apnea database using a set of GARCH models. We discuss the theoretical justification of this approach in the light of the recent developments in heart rate volatility studies. The findings support the value of the Integrated GARCH(1,1) specification in fitting apneic ECG segments implying the presence of shocks to conditional volatility that persist over time. The ARCH(1) model was found superior in fitting normal ECG recordings. These findings provide an important indication to future research that GARCH models can be employed in the development of an apnea screening tool to be used in clinical settings.

The synthesis and characterization of oxotechnetium and oxorhenium mixed-ligand complexes of the general formula MO[NN][S](3) (M = (99)Tc and Re), where NN represents the bidentate ligand 2,2'-bipyridine and S represents a monodentate thiophenol, is reported. The complexes were prepared by ligand exchange reactions using (99)Tc-gluconate and ReOCl(3)(PPh(3))(2) as precursors for the oxotechnetium and oxorhenium complexes, respectively. Compound 1 (M = (99)Tc, S = 4-methylthiophenol) crystallizes in the monoclinic space group P2(1)/a, a = 23.12(1) A, b = 14.349(6) A, c = 8.801(4) A, beta = 94.81(2) degrees, V = 2918(2) A(3), Z = 4. Compound 3 (M = Re, S = 4-methylthiophenol) crystallizes in the monoclinic space group P2(1)/a, a = 23.018(9) A, b = 14.421(5) A, c = 8.775(3) A, beta = 94.78(1) degrees, V = 2903(2) A(3), Z = 4. Compound 4 (M = Re, S = 4-methoxythiophenol) crystallizes in the orthorhombic space group Pbca, a = 16.32(1) A, b = 24.55(2) A, c = 16.94(1) A, V = 6788(9) A(3), Z = 8. In all cases, the coordination geometry around the metal is distorted octahedral with the equatorial plane being defined by the three sulfur atoms of the thiophenols and one nitrogen atom of 2,2'-bipyridine, while the apical positions are occupied by the second nitrogen atom of 2,2'-bipyridine and the oxygen of the M=O core. The complexes are stable, neutral, and lipophilic. Complete (1)H and (13)C NMR assignments are reported for all complexes. The analogous oxotechnetium complexes have been also synthesized at tracer level ((99m)Tc) by mixing the 2,2'-bipyridine and the corresponding thiol with Na(99m)TcO(4) generator eluate using NaBH(4) as reducing agent. Their structure was established by chromatographic comparison with authentic oxotechnetium and oxorhenium complexes using high performance liquid chromatography techniques.

The [NS][S](2) mixed-ligand system was applied to synthesize oxorhenium and oxotechnetium complexes of the general formula MO(o-CH(3)OC(6)H(4)N(CH(2)CH(2))(2)NCH(2)CH(2)S)(p-CH(3)C(6)H(4)S)(2) (M=Re in 1, M=(99)Tc in 2, and M=(99m)Tc in 3). The bidentate [NS] ligand includes the 1-(2-methoxyphenyl)piperazine moiety which is a fragment of the true 5-HT(1A) antagonist WAY 100635. The oxorhenium complex 1 was prepared by a ligand exchange reaction using ReOCl(3)(PPh(3))(2) as precursor while [Bu(4)N][(99)TcOCl(4)] and (99)Tc-gluconate were used as precursors in the synthesis of the oxotechnetium-99 complex 2. Both complexes were characterized by elemental analysis and spectroscopic methods. Crystallographic analysis of 1 showed that the rhenium coordination geometry is trigonal bipyramidal. The basal plane of the trigonal bipyramid is defined by the oxo group and two sulphur atoms, one belonging to the [NS] ligand and the other to an aromatic thiol, while the apical positions are occupied by the nitrogen of the [NS] ligand and the sulphur of the second aromatic thiol. The oxotechnetium-99 complex 2 has almost identical unit cell parameters to those of the oxorhenium complex 1 indicating, in combination with the other analytical data, that the complexes are isostructural. The binding affinity of the oxorhenium complex 1 for the 5-HT(1A) receptor subtype was determined in rat brain hippocampal preparations (IC(50)=106 nM). The oxotechnetium-99m complex 3 was prepared by a ligand exchange reaction using (99m)Tc-glucoheptonate as the precursor. Its structure was established by comparative HPLC studies using the oxotechnetium-99 complex 2 as a reference. Complex 3 was administered by intravenous injection in rats. At 2 min post injection, 0.153% of the injected dose per gram of tissue was measured in rat brain.

Two novel 99mTc-(SNS/S) complexes: a mono-ester compound carrying an ethyl ester group on the tridentate ligand, 99mTcO[C(2)H(5)OOCCH(2)N(CH(2)CH(2)S)(2)][SC(6)H(4)CH(3)], 3, and a diester compound, carrying a second ethyl ester group on the monodentate ligand, 99mTcO[C(2)H(5)OOCCH(2)N(CH(2)CH(2)S)(2)][SC(6)H(4)COOC(2)H(5)], 4, were synthesized. The corresponding oxorhenium(V) complexes, 1 and 2 were also synthesized. Enzymatic hydrolysis demonstrated that 3 remains intact after 10 min incubation while 4 is totally converted to an unidentified hydrophilic complex. Tissue distribution data in mice revealed that both complexes, 3 and 4, exhibit significant initial brain uptake (1.42 and 1.01% of injected dose at 5 minutes post injection respectively) and fast blood clearance.

Two oxorhenium and two oxotechnetium [SN(R)S/S] mixed ligand complexes bearing the phenothiazine moiety on the tridentate ligand SN(R)S have been synthesized and characterized. The corresponding complexes at tracer level (99mTc) have also been prepared.

Two novel [99mTc](SNS/S) mixed ligand complexes carrying a pendant ester function on the monothiolate coligand were synthesized. The corresponding oxorhenium and [99gTc]oxotechnetium complexes prepared at the macroscopic level and chemically characterized were used for structure assignment of [99mTc](SNS/S) complexes prepared at the nanomolar level. Enzymatic hydrolysis of the pendant ester group of [99mTc](SNS/S) mixed ligand complexes by esterase was investigated in vitro and compared with that of the ethyl cysteinate dimer, [99mTc]ECD. Preliminary biodistribution data in mice shows that the complexes are lipophilic and exhibit significant initial uptake in rodent brain.