Tricarbonyltechnetium (I) labelled ligands with nso donor atom set: in vitro and in vivo evaluation

There is an increasing interest for the 99mTc labelling of biomolecules by using bifunctional chelating agents. To find new ligand, which can be linked to the small biomolecules and coordinated with technetium-99m tricarbonyl complexes, is a challenging task. The investigated NSC and NSC5 ligands allow the preparation 99mTc(I) stable complexes in high yield. The 99mTc complexes were characterized by comparing their HPLC profiles with those of the respective Re(I) compounds. Biodistribution and stability studies were carried out, including challenge with histidine. These complexes also proved to be stable in vivo and showed a very good biological behaviour. The radiochemical and biological features of the novel 99mTc complexes, as well as, the nature of the ligands, make them very promising candidates for labelling of tumour specific biomolecules.Physical chemistry 2006 : 8th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 26-29 September 200

99mTc-hexakis-(2-metoxy-isobutyl-isonitrile) ( 99mTc-MIBI) a new myocardial imaging agent: synthesis of MIBI, optimising conditions for radiolabelling with 99mTc at high radiochemical purity and in vivo behavior

99mTc-MIBI is a promising radiopharmaceutical for myocardial perfusion imaging agent, but it has also shown good results in identifying several types of tumors, such as breast, lung and thyroid cancers. It is a lipophilic, cationic technetium (1) complex. In this paper a complete study on the synthesis of 2-metohy-isobutyl-isonitrile (MIBI) as well as a formulation of a lyophilized kit for labeling with 99mTc is presented. Investigation on effective factors as well as finding out the optimum parameters to obtain the highest labelling efficiency and radiochemical purity of 99mTc-MIBI complex were performed. The radiochemical purity of the labelled preparation was high (>95%). Biodistribution study performed in health male Wistar rats showed satisfactory biokinetics results. 99mTc-MIBI was accumulated in sufficient amount into the hearth tissue for myocardial perfusion imaging. MIBI in kit formulation was found to be stable and also safe for administration.Physical chemistry 2006 : 8th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 26-29 September 200

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

Crystal structure of fac-aqua[(E)-4-(benzo[d]thiazol-2-yl)-N-(pyridin-2-ylmethylidene)aniline-κ2N,N′]tricarbonylrhenium(I) hexafluoridophosphate methanol monosolvate

In the title compound, fac-[Re(C19H13N3S)(CO)3(H2O)]PF6·CH3OH, the coordination environment of the ReI atom is octahedral with a C3N2O coordination set. In this molecule, the N,N′ bidentate ligand, (E)-4-(benzo[d]thiazol-2-yl)-N-(pyridin-2-ylmethylidene)aniline, and the monodentate aqua ligand occupy the three available coordination sites of the [Re(CO)3]+ core, generating a `2 + 1' mixed-ligand complex. In this complex, the Re—C bonds of the carbonyl ligands trans to the coordinating N,N′ atoms of the bidentate ligand are longer than the Re—C bond of the carbonyl group trans to the aqua ligand, in accordance with the intensity of their trans effects. The complex is positively charged with PF6− as the counter-ion. In the structure, the complexes form dimers through π–π intermolecular interactions. O—H...O and O—H...N hydrogen bonds lead to the formation of stacks parallel to the a axis, which further extend into layers parallel to (0\overline{1}1). Through O—H...F hydrogen bonds between the complexes and the PF6−counter-anions, a three-dimensional network is established

Development and Pharmacological Evaluation of New Bone-Targeted ^99mTc-Radiolabeled Bisphosphonates

A novel bisphosphonate, 1-(3-aminopropylamino)­ethane-1,1-diyldiphosphonic acid (<b>3</b>), was coupled to the tridentate chelators di-2-picolylamine, 2-picolylamine-<i>N</i>-acetic acid, iminodiacetic acid, 3-((2-aminoethyl)­thio)-3-(1<i>H</i>-imidazol-4-yl)­propanoic acid, and 2-((2-carboxyethyl)­thio)-3-(1<i>H</i>-imidazol-4-yl)­propanoic acid to form ligands <b>6</b>, <b>9</b>, <b>11</b>, <b>15</b>, and <b>19</b>, respectively. Organometallic complexes of the general formula [Re/^99mTc­(CO)₃(κ³-L)] were synthesized, where L denotes ligand <b>6</b>, <b>9</b>, <b>11</b>, <b>15</b>, or <b>19</b>. The rhenium complexes were prepared at the macroscopic level and characterized by spectroscopic methods. The technetium-99m organometallic complexes were synthesized in high yield and were identified by comparative reversed-phase HPLC with their Re analogues. The ^99mTc tracers were stable <i>in vitro</i> and exhibited binding to hydroxyapatite. In biodistribution studies, all of the ^99mTc complexes exhibited high bone uptake superior to that of <b>25</b>, which is the directly ^99mTc-labeled bisphosphonate <b>3</b>, and comparable to that of ^99mTc-methylene diphosphonate (^99mTc-MDP). The tracers [^99mTc­(CO)₃(<b>6</b>)] (<b>26</b>), [^99mTc­(CO)₃(<b>9</b>)] (<b>27</b>), [^99mTc­(CO)₃(<b>11</b>)] (<b>28</b>), and [^99mTc­(CO)₃(<b>15</b>)] (<b>29</b>) exhibited higher bone/blood ratios than ^99mTc-MDP. <b>26</b> had the highest bone uptake at 1 h p.i. The new bisphosphonates showed no substantial growth inhibitory capacity in PC-3, Saos-2, and MCF-7 established cancer cell lines at low concentrations. Incubation of <b>26</b> with the same cancer cell lines indicated a rapid and saturated uptake. The promising properties of <b>26</b>–<b>29</b> indicate their potential for use as bone-imaging agents

Crystal structure of fac-tricarbonyl(quinoline-2-carboxylato-κ2N,O)(triphenylarsane-κAs)rhenium(I)

In the title compound, [Re(C10H6NO2)(CO)3{As(C6H5)3}], the coordination environment of ReI is that of a distorted octahedron. Three coordination sites are occupied by three carbonyl groups in a facial arrangement and the remaining three sites by triphenylarsane and deprotonated quinaldic acid in As-mono- and N,O-bidentate fashions, respectively. In the crystal, the complexes are linked through weak C—H...O hydrogen bonds, forming a three-dimensional network. It worth noting that, as far as we know, this complex is the first ReI triphenylarsane tricarbonyl compound to be reported

Design, synthesis, structural optimization, SAR, in silico prediction of physicochemical properties and pharmacological evaluation of novel & potent thiazolo[4,5-d]pyrimidine corticotropin releasing factor (CRF) receptor antagonists

Corticotropin-releasing factor (CRF) is a 41-amino-acid neuropeptide secreted from the hypothalamus and is the main regulator of the hypothalamus-pituitary-adrenocortical (HPA) axis. CRF is the master hormone which modulates physiological and behavioral responses to stress. Many disorders including anxiety, depression, addictive disorders and others are related to over activation of the CRF system. This suggests that new molecules which can interfere with CRF binding to its receptors may be potential candidates for neuropsychiatric drugs to treat stress-related disorders. Previously, three series of pyrimidine and fused pyrimidine CRF receptor antagonists were synthesized by our group and specific binding assays, competitive binding studies and determination of the ability to antagonize the agonist-stimulated accumulation of cAMP (the second messenger for CRF receptors) were reported. In continuation of our efforts in this direction, in the current manuscript, we report the synthesis & biological evaluation of a new series of CRF receptor antagonists. Seven compounds showed promising binding affinity with the best two compounds (compounds 6 & 43) displaying a superior binding affinity to all of our previous compounds. Compounds 6 & 43 have only 4 times and 2 times less binding affinity than the standard CRF antagonist antalarmin, respectively. Thus, our two best lead compounds (compound 6 & 43) can be considered potent CRF receptor antagonists with binding affinity of 41.0 & 19.2 nM versus 9.7 nM for antalarmin

Evaluation of Rhenium and Technetium-99m Complexes Bearing Quinazoline Derivatives as Potential EGFR Agents

Τhe Epidermal Growth Factor Receptor tyrosine kinase inhibitor (EGFR-TKI) 6-amino-4-[(3-bromophenyl) amino]quinazoline was derivatized with 6-bromohexanoyl-chloride and coupled with the tridentate chelating agents N-(2-pyridylmethyl) aminoethyl acetic acid (PAMA) and L(+)-cysteine bearing the donor atom set NNO and SNO, respectively. The rhenium precursors ReBr(CO)5 and fac-[NEt4]2[ReBr3(CO)3] were used for the preparation of the Re complexes fac-[Re(NNO)(CO)3] (5a) and fac-[Re(SNO)(CO)3] (7a) which were characterized by NMR and IR spectroscopies. Subsequently, the new potential EGFR inhibitors were labeled with the fac-[99mTc(CO)3]+ core in high yield and radiochemical purity (>90%) by ligand exchange reaction using the fac-[99mTc][Tc(OH2)3(CO)3]+ precursor. The radiolabeled complexes were characterized by comparative HPLC analysis with the analogous rhenium (Re) complexes as references. In vitro studies in the A431 cell lines showed that both ligands and Re complexes inhibit A431 cell growth. Complex 5a demonstrated the highest potency (IC50 = 8.85 ± 2.62 μM) and was further assessed for its capacity to inhibit EGFR autophosphorylation, presenting an IC50 value of 26.11 nM. Biodistribution studies of the 99mTc complexes in healthy mice showed high in vivo stability for both complexes and fast blood and soft tissue clearance with excretion occurring via the hepatobiliary system