Ulderico Mazzi

Crystal structures of technetium compounds

A. B. C. D. E. F. Introduction .__ _......_._ _.._....._....._...._........_....._ _ 191 Remarks . . . . . . . . .._ _..~ ~._.. 193 Oxides, technetate, and pertechnetate compounds _ _ _ _ . . . _ _ _ _ _ _ _ _ . . _ _ _ _ _ . . 194 Halideandoxyhalidecompounds _____.______...___.______________.... 195 Polyhalide and polypseudohalide complexes . _ . _ _ . _ . . _ . _ . . . . . . . . _ _ _ . . . . . 197 Complexes _._..._ _ _ _ _ _ _ _ _ _...._._ _ _ _ _ _ __.._ _ ___ _._.._ _ _ ___... 199 (i) Complexes containing Ir-acceptor ligands _ . . . . . . . _ _ _ . . . . _ _ _ _ . . . . . _ _ _ 199 (ii) Complexes containing the TFO group . _ _ . . _ . . . . . . . . . . . . . . . . . . . . . . 208 (iii) Othercomplexes 211 G. Miscellaneous 215 H.Conclusions ___......___ .... 216 (i) General 216 (ii) Bondlengths 218 (iii) Summary 222 Acknowledgments 224 References 224

Radiochemical and biological characteristics of 99mTc-UBI 29-41 for imaging of bacterial infections

A technetium-99m-labeled peptide derived from ubiquicidine, further referred to as 99mTc-UBI 29-41, targets bacterial and fungal infections, but not sterile inflammatory processes, in experimental animals. This paper reports on the radiochemical and biological features of this radioactive agent and the importance of the amino acid sequence of UBI 29-41 for imaging of infections. Radiochemical analyses of 99mTc-UBI 29-41 and a radiolabeled scrambled version of this peptide, i.e. 99mTc-Sc-UBI 29-41, revealed that both peptides were labeled rapidly (within 10 min) and effectively with little colloid formation (less than 5% of the total radioactivity) and very little free pertechnetate (or radioactive intermediates) in the preparations containing radiolabeled peptide. Furthermore, association of the peptides with bacteria could be competed with excess unlabeled peptide and this association proved to be temperature-dependent. Based on this in vitro data we concluded that labeling of peptides with 99mTc by this direct method is rapid, efficient, and safe. Scintigraphy demonstrated that radioactivity is rapidly removed from the circulation (half-lifes of UBI 29-41 and Sc-UBI 29-41 were 16 and 21 min, respectively) mainly by renal clearance. Analysis of murine blood revealed that only a small proportion of the intravenously injected 99mTc-peptides is associated with blood cells. Although both radiolabeled peptides accumulated rapidly at sites of infection, the values for 99mTc-UBI 29-41 were higher (P < 0.05) than for 99mTc-Sc-UBI 29-41. Moreover, injection of excess unlabeled UBI 29-41, but not Sc-UBI 29-41, into Staphylococcus aureus-infected mice prior to injection of 99mTc-UBI 29-41 significantly (P < 0.05) reduced the accumulation of this radiopharmaceutical at the site of infection. In addition, we observed significantly (P < 0.01) higher amounts of 99mTc-UBI 29-41 at the site of infection in mice using a carrier-free radiolabeled UBI 29-41 as compared with unpurified preparations containing radiolabeled UBI 29-41. This in vivo data indicates that the amino acid sequence of 99mTc-UBI 29-41 contributes to its accumulation at the site of infection.

Inhibition of Hepatocellular Carcinomas in vitro and Hepatic Metastases in vivo in Mice by the Histone Deacetylase Inhibitor HA-But

Purpose: The purpose is to evaluate the CD44-mediated cellular targeting of HA-But, a hyaluronic acid esterified with butyric acid (But) residues, to hepatocellular carcinoma cell lines in vitro and to hepatic tumor metastases in vivo. Experimental Design: In vitro, the CD44-dependent cytotoxicity in two human hepatocellular carcinoma cell lines (HepB3 and HepG2) with high and low CD44 expression was investigated; in vivo, the effect on liver metastases originating from intrasplenic implants of Lewis lung carcinoma (LL3) or B16-F10 melanoma in mice was compared with the pharmacokinetics of organ and tissue distribution using different routes of administration. Results: HepB3 and HepG2 cell lines showed different expression of CD44 (78 and 18%, respectively), which resulted in a CD44-dependent HA-But inhibitory effect as demonstrated also by the uptake analysis performed using radiolabeled HA-But (99mTc-HA-But). Pharmacokinetic studies showed different rates of 99mTc-HA-But distribution according to the route of administration (i.v., i.p., or s.c.): very fast (a few minutes) after i.v. treatment, with substantial accumulation in the liver and spleen; relatively slow after i.p. or s.c. treatment, with marked persistence of the drug at the site of injection. The effect of s.c. and i.p. treatment with HA-But on liver metastases originating from intrasplenic implants of LL3 carcinoma or B16-F10 melanoma (both CD44-positive: 68 and 87%, respectively), resulted in 87 and 100% metastases-free animals, respectively (regardless of the route of administration), and a significant prolongation of the life expectancy compared with control groups. Conclusions: HA-But tends to concentrate in the liver and spleen and appears to be a promising new drug for the treatment of intrahepatic tumor lesions.

18F-labeled radiopharmaceuticals for PET in oncology, excluding FDG

This article reviews possible use of (18)F-labelled radiopharmaceuticals in oncology with positron emission tomography. The characteristics of various (18)F-labelled compounds are proteins and peptides, those that bind to. receptors, agents to assess hypoxia, and agents to evaluate gene therapy are highlighted. Furthermore, different (18)F-labelled tissue specific agents are indicated for the detection and monitoring of various malignancies: melanoma, brain tumours, breast cancer, prostate cancer and colorectal cancer. (18)F-fluorodeoxyglucose has been excluded from this summary.

A Paclitaxel-Hyaluronan Bioconjugate Targeting Ovarian Cancer Affords a Potent In vivo Therapeutic Activity

Purpose: This study was designed to evaluate the pharmacologic and biological properties of a paclitaxel-hyaluronan bioconjugate (ONCOFID-P) against IGROV-1 and OVCAR-3 human ovarian cancer xenografts following i.p. administration. Experimental Design:In vitro tumor sensitivity to ONCOFID-P was analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, whereas bioconjugate interaction with cells was studied cytofluorimetrically and by confocal microscopy. In vivo toxicity was assessed by a single-dose maximum-tolerated dose, peripheral blood cell count determination and by histologic analysis. Biodistribution of the compound was evaluated with a small animal–dedicated scintigraphy gamma camera following injection of 99mTc-labeled ONCOFID-P. Pharmacokinetic analysis was also carried out. Female severe combined immunodeficiency mice implanted with ovarian cancer cells underwent treatment with ONCOFID-P or free paclitaxel starting from day 7 or 14 after tumor injection, and survivals were compared. Results: ONCOFID-P interacted with CD44, entered cells through a receptor-mediated mechanism, and exerted a concentration-dependent inhibitory effect against tumor cell growth. After i.p. administration, the bioconjugate distributed quite uniformly within the peritoneal cavity, was well-tolerated, and was not associated with local histologic toxicity. Pharmacokinetic studies revealed that blood levels of bioconjugate-derived paclitaxel were much higher and persisted longer than those obtained with the unconjugated free drug. Intraperitoneal treatment of tumor-bearing mice with the bioconjugate revealed that ONCOFID-P exerted a relevant increase in therapeutic activity compared with free drug. Conclusions: ONCOFID-P significantly improved results obtained with conventional paclitaxel, in terms of in vivo tolerability and therapeutic efficacy; these data strongly support its development for locoregional treatment of ovarian cancer.

Technetium-99m labelled fluconazole and antimicrobial peptides for imaging of Candida albicans and Aspergillus fumigatus infections

Abstract. The aim of this study was to investigate whether technetium-99m labelled fluconazole can distinguish fungal from bacterial infections. Fluconazole was labelled with 99mTc and radiochemical analysis showed less than 5% impurities. The labelling solution was injected into animals with experimental infections. For comparison, we used two peptides for infection detection, i.e. UBI 29–41 and hLF 1–11, and human IgG, all labelled with 99mTc. Mice were infected with Candida albicans or injected with heat-killed C. albicans or lipopolysaccharides to induce sterile inflammation. Also, mice were infected with Staphylococcus aureus or Klebsiella pneumoniae. Next, accumulation of 99mTc-fluconazole and 99mTc-labelled peptides/IgG at affected sites was determined scintigraphically. 99mTc-fluconazole detected C. albicans infections (T/NT ratio=3.6±0.47) without visualising bacterial infections (T/NT ratio=1.3±0.04) or sterile inflammatory processes (heat-killed C. albicans: T/NT ratio=1.3±0.2; lipopolysaccharide: T/NT ratio=1.4±0.1). C. albicans infections were already seen within the first hour after injection of 99mTc-fluconazole (T/NT ratio=3.1±0.2). A good correlation (R2=0.864; P<0.05) between T/NT ratios for this tracer and the number of viable C. albicans was found. Although 99mTc-UBI 29–41 and 99mTc-hLF 1–11 were able to distinguish C. albicans infections from sterile inflammatory processes in mice, these 99mTc-labelled peptides did not distinguish these fungal infections from bacterial infections. It is concluded that 99mTc-fluconazole distinguishes infections with C. albicans from bacterial infections and sterile inflammations.

Complexes of technetium(IV) and (III) with tertiary phosphines

Abstract The synthesis and characterization of the complexes trans-TcX4L2 and mer-TcX3L3 (X = Cl and Br, and L = PMe2Ph, PEt2Ph and PPh3) are reported. Configurations were deduced by far-IR and 1H NMR studies. Magnetic susceptibility and 1H NMR results for mer-TcCl3(PMe2Ph)3 are compared with those for analogues d4 complexes.

Synthesis, characterization and electrochemical studies on technetium(V) and rhenium(V) oxo-complexes with N,N'-2-hydroxypropane-1,3-bis(salicylideneimine)

Ligand-exchange reactions of potential quinquedentate Schiff base ligands derived from salicylaldehyde and 1,3-diamino-2-hydroxypropane (H 3 L) with [MOCl 4 ] − (M = Tc and Re) have been investigated. The complexes [MOCl 2 (ROH)(H 2 L·HCl)] ( I ) (R = Me, Et), [ReOCl(HL)] ( II ) and μ-O[MO(HL)] 2 ( III ) were synthesized and characterized by the usual physicochemical measurements. Cyclic voltammetries for both III complexes reveal two separate and single-electron redox processes. The crystal structure of μ-O[TcO(HL)] 2 was determined by single-crystal X-ray diffraction methods. Crystals are monoclinic, space group P 2 1 / c , with a = 9.423(6), b = 19.666(9), c = 22.785(11) A, β = 99.41(4)° and Z = 4. X-ray diffraction provides 2842 observed reflections (up to θ = 40°) and the structure has been refined by full-matrix least-squares methods to R = 0.10. The ‘dimeric’ structure of μ-O[TcO(HL)] 2 consists of two distorted octahedral TcO(HL) moieties bridged by an oxygen atom which occupies the sixth coordination site of each moiety with the TcOTc angle nearly linear (173°).

Rhenium(V) oxo complexes with schiff base ligands containing four or five coordination sites. X-ray molecular structure of [N,N′-3-azapentane-1,5-diylbis(salicylideneiminato)(3-)-O,O′,N,N′,N″]oxorhenium(V)

Abstract The reactions of [ReOCl4]− with Schiff base ligands derived from salicylaldehyde and 1,5-diamino- pentane (H2L1a), -hexane (H2L1b), -heptane (H2L1c) or diethylentriamine (H3L2) have been investigated. The complexes ReOCl2(EtOH)HL1n (I) (n=a, b or c), Re2O2(MeOH)2Cl4HL2 (II), ReOClL1n (III) and ReOL2 (IV), have been synthesized and characterized with the usual physicochemical measurements. The crystal structure of ReOL2 was determined by single crystal X-ray methods. Crystals are monoclinic, space group P21/c, with a=9.470(7), b=9.358(8), c=21.859(12) A, β=99.23(8)16° and Z=4. X-ray diffraction provides 5601 observed reflections (up to 2⊖=60°) and the structure has been refined by full-matrix least-squares methods to R=0.061. The monomeric structure consists of distorted octahedral ReOL2 units. One oxygen atom of the N3O2 pentadentate ligand is located trans to the rheniumoxo oxygen bond, while the remaining four coordinating atoms lie on the equatorial plane of the octahedron assuming that the oxo-oxygen occupies an apex. The arrangement of the two iminophenolate groups is explained as a function of the length of the aliphatic chain joining the two imine groups.

Monooxorhenium(V) complexes with the tridentate Schiff baseN-(2-hydroxyphenyl)salicylideneimine

SummaryThe reactions of the tridentate Schiff base ligandN-(2-hydroxyphenyl) salicylideneimine (HOPhsalH) with oxotetrachlororhenate (IV) have been investigated. The complexes (Bu4N)[ReOCl3(HOPhsal)], (Bu4N)[ReOCl2(OPhsal)],cis- [ReOCl(MeOH)(OPhsal)],trans-[ReOCl(MeOH)(OPhsal)] (1), trans-[ReOCl(OH2)(OPhsal)] · Et2O (2), trans-[ReOCl(OH2)(OPhsal)] · Me2CO,cis-[ReOCl(PPh3)(OPhsal)],cis-[ReOCl(PMe2Ph)(OPhsal)](3) have been synthesized and characterized. The crystal structures of(1), (2) and(3) have been solved from three-dimensional x-ray data by Patterson and Fourier methods and refined by least-squares methods to R 0.10 for(1), 0.042 for(2) and 0.059 for(3). In all the three complexes, the ligands surrounding the rhenium atom are at the apices of a distorted octahedron, with the equatorial ONO donor atoms of the tridentate Schiff base bent away from the Ooxo and toward the loosely bound MeOH in(1), H2O in(2) and Cl in(t3). The fourth equatorial substituent is Cl (1 and2) and PMe2Ph(3) and the rhenium atoms lie 0.30–0.37 Å above the best plane through the four equatorial atoms, in the direction of the Ooxo. All interatomic distances and angles are normal.