Imaging in situ breast carcinoma (with or without an invasive component) with technetium-99m pentavalent dimercaptosuccinic acid and technetium-99m 2-methoxy isobutyl isonitrile scintimammography

INTRODUCTION: The aim of the study was to retrospectively define specific features of the technetium-99m pentavalent dimercaptosuccinic acid ((99m)Tc-(V)DMSA) and technetium-99m 2-methoxy isobutyl isonitrile ((99m)Tc-Sestamibi [(99m)Tc-MIBI]) distribution in ductal breast carcinoma in situ and lobular breast carcinoma in situ (DCIS/LCIS), in relation to mammographic, histological and immunohistochemical parameters. MATERIALS AND METHODS: One hundred and two patients with suspicious palpation or mammographic findings were submitted preoperatively to scintimammography (a total of 72 patients with (99m)Tc-(V)DMSA and a total of 75 patients with (99m)Tc-Sestamibi, 45 patients receiving both radiotracers). Images were acquired at 10 min and 60 min, and were evaluated for a pattern of diffuse radiotracer accumulation. The tumor-to-background ratios were correlated (T-pair test) with mammographic, histological and immunohistochemical characteristics. RESULTS: Histology confirmed malignancy in 46/102 patients: 20/46 patients had DCIS/LCIS, with or without coexistent invasive lesions, and 26/46 patients had isolated invasive carcinomas. Diffuse (99m)Tc-(V)DMSA accumulation was noticed in 18/19 cases and (99m)Tc-Sestamibi in 6/13 DCIS/LCIS cases. Epithelial hyperplasia demonstrated a similar accumulation pattern. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value for each tracer were calculated. Solely for (99m)Tc-(V)DMSA, the tumor-to-background ratio was significantly higher at 60 min than at 10 min and the diffuse uptake was significantly associated with suspicious microcalcifications, with the cell proliferation index ≥ 40% and with c-erbB-2 ≥ 10%. CONCLUSION: (99m)Tc-(V)DMSA showed high sensitivity and (99m)Tc-Sestamibi showed high specificity in detecting in situ breast carcinoma ((99m)Tc-(V)DMSA especially in cases with increased cell proliferation), and these radiotracers could provide clinicians with preoperative information not always obtainable by mammography

Convenient route leading to neutral fac-M(CO)3(NNO) complexes (M = Re, 99mTc) coupled to amine pharmacophores

The synthesis and characterization of three neutral tricarbonyl fac-M(CO)3(NNO) (M = Re, 99mTc) 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 nucleophites. The rhenium complexes were synthesized using the [NEt 4]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 (99mTc(CO)3(H2O) 3]+ precursor. The reaction scheme presented for the synthesis of the fac-M(CO)3(NNO) (M = Re, 99mTc) 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. © 2008 American Chemical Society

A new bifunctional tridentate NSN ligand leading to cationic tricarbonyl fac- M(NSN)(CO)(3) (+) (M = Re, Tc-99m) complexes

The synthesis and characterization of the new NSN tridentate bifunctional chelating agent 3-[2-(2'-pyridin-2-yl-ethylsulfanyl)ethylamino] propionic acid (as its hydrochloric salt, 1) and of its corresponding rhenium comp lex fac-[Re(NSN)(CO)(3)](+), 2, is described. Both compounds were characterized by elemental analysis, IR and NMR spectroscopies and X-ray crystallography. In complex 2 the coordination geometry around rhenium is distorted octahedral with the NSN atoms participating in the coordination sphere while the carboxylate group remains free. At tracer level, the analogous complex fac-[Tc-99m(NSN)(CO)(3)](+), 3, was obtained in high yield by reacting ligand 1 with the fac-[Tc-99m(H2O)(3)(CO)(3)](+) precursor at pH 6.5. The structure of 3 was established by HPLC comparison to the prototype rhenium comp lex 2. Complex 3 is stable in solution as well as in the presence of strongly coordinating agents like histidine or cysteine. Our data indicate that ligand 1 can be used as a bifunctional NSN chelating agent in the design of potential Tc-99m-radiopharmaceuticals. (C) 2013 Elsevier B.V. All rights reserved

Synthesis, characterization and evaluation of 68Ga labelled monomeric and dimeric quinazoline derivatives of the HBED-CC chelator targeting the epidermal growth factor receptor

Tyrosine kinase (TK) receptors including epidermal growth factor receptors (EGFRs) are known to be overexpressed in a wide variety of solid tumors associated with poor prognosis. The HBED-CC chelator N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid 1 was coupled via one or both its propionic acid moieties with the quinazoline EGFR-TK inhibiting pharmacophore 4-amino-N-(4-((3-bromophenyl)amino)quinazolin-6-yl)butanamide 3 resulting in either a monomeric 4 or a dimeric 5 species. Ligands 4 and 5 reacted with Ga3+ generating the corresponding complexes Ga4 and Ga5. Both ligands and complexes were characterized with mass spectrometry and NMR spectroscopy and evaluated in vitro with MTT assays in A431 cells, where they showed IC50 values in the range 51.6 to 68.8 μM. Labeling of ligands 4 and 5 with the PET radionuclide 68Ga was quantitative and resulted in tracers [68Ga]Ga4 and [68Ga]Ga5 with radiochemical purities greater than 98%, which were also characterised by comparative RP-HPLC studies with Ga4 and Ga5 respectively. Radiotracers [68Ga]Ga4 and [68Ga]Ga5 were stable (intact tracer over 98%) in the reaction mixture (120 min) and in human serum (30 min). Both tracers were evaluated in vivo with biodistribution experiments in SCID mice bearing A431 tumors presenting tumor uptake of 1.34 for [68Ga]Ga4 and 1.01 %ID/g for [68Ga]Ga5 at 5 min, which was slightly decreased at 60 min p.i. and then remained stable until 120 min p.i. To the best of our knowledge, this is the first report of monomeric and dimeric quinazoline conjugates with the chelator HBED-CC, which can serve as a basis for further development of EGFR-TKI targeting tracers. © 2020 Elsevier Inc

Solid-phase synthesis of a peptide derivative of thymosin alpha1 and initial studies on its 99mTc-radiolabelling

A derivative (1) of the immunopotentiating 28-peptide thymosin alpha1 has been especially designed, so that it can be 99mTc-radiolabelled, and synthesized following the Fmoc solid-phase peptide synthesis approach. Derivative 1 contains the N-terminal fragment Tα1[1-14] as a bioactive segment, at the C-terminus of which a 99mTc-chelating moiety consisting of Nα,Nα-dimethylglycine, serine and cysteine is linked through the Nε-amino group of a 'bifunctional' lysine residue; the latter is indirectly anchored on the solid-phase peptide synthesis resin through 6-aminocaproic acid (dmGSCK{N ε-Tα1[1-14]}Aca). Synthetic derivative 1 was obtained at high overall yield (approximately 35%) and purity (>95%) and shown to be efficiently radiolabelled with 99mTc, thus resulting in the first, to our knowledge, so far reported 99mTc-radiolabelled derivative of thymosin alpha1, which may be eventually used as a specific molecular tool for the in vitro/in vivo study of the mode of action of the parent bioactive peptide. © 2007 The Authors

Specific in vitro binding of a new 99mTc-radiolabeled derivative of the C-terminal decapeptide of prothymosin alpha on human neutrophils

Prothymosin alpha (ProTα) is a conserved mammalian polypeptide with intracellular functions associated with cell proliferation and apoptosis and an extracellular role associated with immunopotentiation. The N-terminal fragment [1-28], which is identical with the immunostimulating peptide thymosin α1 (Tα1), was earlier considered as the immunoactive region of the polypeptide; however, recent data suggest that ProTα may exert a discrete immunomodulating action through its central or C-terminal region, via targeting Toll-like receptor- 4 (TLR4). In this work, a derivative of the C-terminal fragment ProTα[100-109] (ProTα-D1) that can be radiolabeled with 99mTc was developed. The biological activity of the non-radioactive 185/187rhenium-complex of this derivative ([185/187Re]ProTα-D1, structurally similar with [99mTc]ProTα-D1) was verified through suitable in vitro bioassays on human neutrophils. Subsequent cell-binding studies revealed specific, time-dependent and saturable binding of [99mTc]ProTα-D1 on neutrophils, which was inhibited by intact ProTα and ProTα[100-109], as well as by a "prototype" TLR4-ligand (lipopolysaccharide from Escherichia coli). Overall, our results support the existence of ProTα-binding sites on human neutrophils, recognizing [99mTc]ProTα-D1, which might involve TLR4. [99mTc]ProTα-D1 may be a useful tool for conducting further in vitro and in vivo studies, aiming to elucidate the extracellular mode of action of ProTα and, eventually, develop ProTα-based immunotherapeutics. © 2015 Elsevier B.V

Synthesis and structural characterization of neutral "3+2" oxorhenium and oxotechnetium complexes of the 2-mercaptoethyl-N-glycine (SNO)/2,2 '-bipyridine (NN) mixed ligand system

Neutral. hexacoordinated "3 + 2" mixed ligand oxorhenium (1) and oxotechnetium (2) complexes of the general formula MO [SNO][NN]. where M = Re or Tc-99, SNO is 2-mercaptoethyl-N-glycine and NN is 2,2'-bipyridine (bpy), were synthesized by simultaneous action of the tridentate SNO and the bidentate NN ligand on ReOCl3(PPh3)(2) or (TcO)-Tc-99-gluconate precursors in a 1: 1: 1 molar ratio. Both complexes were characterized by elemental analysis, IR and NMR spectroscopy. X-ray structure determination of rhenium complex I revealed a distorted octahedral coordination geometry where the SNO donor atoms of the tridentate ligand and one bpy nitrogen atom occupy the equatorial positions of the octahedron, whereas the second bpy nitrogen atom and the oxo-group fill the apical positions. (c) 2007 Elsevier B.V. All rights reserved

Oxotechnetium (TcO)-Tc-99m[SN(R)S][S] complexes as potential 5-HT1A receptor imaging agents

A series of (TcO)-Tc-99m[SN(R)S][S] complexes carrying the 1-(2-methoxyphenyl)piperazine moiety on the tridentate ligand [SN(R)S] was synthesized. For structural characterization and for in vitro binding assays the analogous oxorhenium complexes were prepared. As demonstrated by appropriate competition binding tests in rat hippocampal preparations, all oxorhenium analogues showed affinity for the 5-HT1A receptor binding sites with IC50 values at the nanomolar range (IC50 = 5.8-103 nM). All (TcO)-Tc-99m[SN(R)S]/[S] complexes showed significant brain uptake in rats at 2 min p.i. (0.24-1.31% ID). However, a clear correlation between distribution of radioactivity in the brain and distribution of 5-HT1A receptors could not be established. (C) 2002 Elsevier Science Inc. All rights reserved