Bernhard Noll

Comparison of [18F]FHPG and [124/125I]FIAU for imaging herpes simplex virus type 1 thymidine kinase gene expression

Abstract. Various radiotracers based on uracil nucleosides (e.g. [124I]2-fluoro-2-deoxy-5-iodo-1-β-D-arabinofuranosyluracil, [124I]FIAU) and acycloguanosine derivatives (e.g. [18F]9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]guanine, [18F]FHPG) have been proposed for the non-invasive imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene expression. However, these radiotracers have been evaluated in different in vitro and in vivo models, precluding a direct comparison. Therefore, we directly compared [18F]FHPG and radioiodinated FIAU to assess their potential for PET imaging of transgene expression. The uptake of [125I]FIAU, [18F]FHPG and [3H]acyclovir was determined in vitro using four different HSV1-tk expressing cell lines and their respective negative controls. The in vitro tracer uptake was generally low in non-transduced parental cell lines. In HSV1-tk expressing cells, [3H]acyclovir showed approximately a twofold higher tracer accumulation, the [18F]FHPG uptake increased by about sixfold and the [125I]FIAU accumulation increased by about 28-fold after 120-min incubation of T1115 human glioblastoma cells. Similar results were found in the other cell lines. In addition, biodistribution and positron emission tomography (PET) studies with [18F]FHPG and [124/125I]FIAU were carried out in tumour-bearing BALB/c mice. Significantly higher specific accumulation of radioactivity was found for [125I]FIAU compared with [18F]FHPG. The ratio of specific tracer accumulation between [125I]FIAU and [18F]FHPG increased from 21 (30xa0min p.i.) to 119 (4xa0h p.i.). PET imaging, using [124I]FIAU, clearly visualised and delineated HSV1-tk expressing tumours, whereas only a negligible uptake of [18F]FHPG was observed. This study demonstrated that in vitro and in vivo, the radioiodinated uracil nucleoside FIAU has a significantly higher specific accumulation than the acycloguanosine derivative [18F]FHPG. This suggests that [124I]FIAU should be the preferred reporter probe for PET imaging of HSV1-tk gene expression. Thus, further attempts to develop suitable PET tracers for the assessment of HSV1-tk gene expression should also focus on 18F-labelled uracil derivatives.

Yttrium-86-labelled human serum albumin microspheres: relation of surface structure with in vivo stability

INTRODUCTIONnRadiolabelled particles are an attractive tool in the therapy of malignancies of the liver. We consider particles manufactured from denatured human serum albumin (HSA) as useful carriers of therapeutic radionuclides. Covalent attachment of suitable chelators onto the surface of the spheres promises an easy access to radiolabelled HSA microspheres.nnnMETHODSnWe synthesized 1,4,7,10-tetraazacyclododecane-N,N,N,N-tetraacetic acid (DOTA) bearing smooth, medium-rough and rough surfaced HSA microspheres (mean diameter: 25 microm). In vitro stability of 86 Y-labelled particles was determined after incubation in human plasma and in a DTPA challenge experiment. In vivo stability of 86 Y DOTA-HSA microspheres was determined after single intravenous application in rats. Subsequently, the particles were completely trapped in the lung microvasculature. Thus, the lung serves in our experiments as target organ.nnnRESULTSnDOTA-HSA microspheres were 86 Y labelled in reproducible high yields (>95%). No differences between smooth and rough surfaced spheres were found for both DOTA coupling and 86 Y labelling. Labelled microspheres showed high in vitro stability in human plasma and in DTPA solution with only 8+/-1% and 2+/-0% loss of radioactivity from the surface, respectively, 48 h postinjection (pi). The three batches (smooth, medium-rough and rough surfaced microspheres) differed considerably in their radioactivity recovery in the lungs of rats 48 h pi. Smooth particles showed the highest in vivo stability of the radiolabel on the surface of the spheres, presumably because of slower proteolytic degradation.nnnCONCLUSIONnWe found that for the preparation of HSA-derived microspheres for radiotherapeutic application, smooth surfaced spheres are superior to rough spheres due to their higher in vivo stability of the radionuclide fixation.

Technetium and rhenium complexes of mercapto-containing peptides 1. Tc(V) and Re(V) complexes with mercaptoacetyl diglycine (MAG2) and X-ray structure of AsPh4[TcO(MAG2)]·C2H5OH

Abstract The reaction of mercaptoacetyl diglycine (MAG 2 ) with technetium(V) gluconate in aqueous solution produced [TcO(MAG 2 )] − . A single X-ray structure determination was carried out for the tetraphenylarsonium salt. The dark brown crystals are monoclinic, space group P 2( 1 )/ n , with a =12.478(5), b =14.922(5), c =17.183(9) A and Z =4. The [TcO(MAG 2 )] − ion has a square pyramidal geometry with the technetium atom displaced by 0.756 A towards the oxo ligand from the plane formed by the equatorial S,N,N,O atoms. The rhenium complex AsPh 4 [ReO(MAG 2 )] was prepared analogously starting from Re(V) gluconate and characterized.

Sources of radiochemical impurities in the 99mTc/S-unprotected MAG3 system.

With the aim of obtaining a general insight into the technetium/S-unprotected MAG3 system, the reactions of technetium with the unprotected MAG3 ligand, both at c.a.- and n.c.a.-level, were investigated. Based on a profound knowledge of the reaction route and the TcMAG3 complexes, sources of by-products were identified and eliminated as far as possible. Only a small percentage (< 5%) of intermediate Tc-MAG3 complexes occurs, but this may increase by improper handling of the kit, such as insufficient reaction time. In conclusion, two kinds of impurity may occur in the Tc/MAG3 kit: One is derived from impurities in the ligand (MAG3 disulphide), which can be excluded by careful preparation and storage. The other is caused by insufficient reaction time according to the scheme (Fig. 3) during the labelling procedure. Its content can be minimized by optimization of the reaction time. A reaction time of at least 10 minutes gives about 98% of the renal agent.

Technetium and rhenium complexes of mercaptoacetyl glycine ligands 2. Formation and molecular structure of Re(V) complexes with mercaptoacetyl glycine and mercaptoacetyl glycine ethylester

Abstract Reaction of [ReOCl 4 ] − with mercaptoacetyl glycine (MAG 1 ) in a 1:1 ratio gives [ReO(MAG 1 )Cl] − . Using an excess of the ligand in ethanol, a neutral oxorhenium(V) complex [ReO(MAGEt 1 ) 2 ] is formed where the metal is coordinated by S and N of one ligand, and by S and O (amide group) of the other ligand molecule. The carboxylic groups of both mercaptoacetyl glycine ligands have been esterified with the solvent ethanol. Both complexes were characterized by X-ray crystallography.

Synthesis and Enzymatic Evaluation of Nucleosides Derived from 5-Iodo-2'-Halo-2'-Deoxyuridines

The synthesis of new nucleosides by alkenylation of 5-iodo-2’-halo-2’-deoxyuridines with E-(1-tributylstannyl)-propene-1-ol via STILLE-coupling is described. The new compounds are characterized by 1H NMR and elemental analysis. All nucleosides are evaluated by an enzymatic assay to be substrates of herpes simplex virus type 1 thymidine kinase (HSV-1 TK) and compared with uridine, thymidine and (E)-5-(2-iodovinyl)-2’-fluoro-2’-deoxyuridine (IVFRU).

Preparation and structural studies of neutral oxorhenium(V) complexes with D-penicillamine methyl ester

Reaction of oxorhenium(V) gluconate with D-penicillamine methyl ester (methyl 3-sulfanylvalinate) yielded three neutral 1∶2 complexes. For two complexes (1 and 2) the 1H NMR spectrum in (CD3)2SO shows the presence of a deprotonated and a neutral nitrogen donor group in the ReO(NS)2 system which is an unusual co-ordination mode for bidentate N,S ligands. Complex 1, [ReO{SC(CH3)2CH(CO2CH3)NH2}{SC(CH3)2CH(CO2CH3)NH}], possibly containing in non-co-ordinating solvents an ester oxygen co-ordinated trans to the ReO group, is able to bind a water molecule trans to the oxo core to give species 2. In aqueous solution the mixed-ligand complex [ReO{SC(CH3)2CH(CO2CH3)NH2}{SC(CH3)2CH(CO2)NH2}] 3 was unexpectedly formed out of 1 and 2. It contains bidentate D-penicillamine methyl ester and tridentate D-penicillamine in a co-ordination geometry similar to that of the known D-penicillamine complex [ReO{SC(CH3)2CH(CO2H)NH2}{SC(CH3)2CH(CO2)NH2}] 4. Complexes 3 and 4 were structurally characterized by X-ray diffraction.

(4‐Methoxybenzenethiolato‐κS)oxido[2,2′‐(propylimino)bis(ethanethiolato)‐κ3S,N,S′]rhenium(V)

The central Re atom of the mononuclear title complex, [Re(C8H18NS2)(C6H4OS)O], is five-coordinate (ReNOS3) with a square-pyramidal geometry comprising a tridentate 2,2′-(propylxadimino)diethanethiolxadate ligand, a 4-methoxyxadbenzenexadthiolxadate ligand and a doubly-bonded O atom.

Two mononuclear Tc complexes: [2,2'-(3-phenylpropylimino)- and [2,2'-(propylimino)bis(ethanethiolato)](4-methoxybenzenethiolato)oxidotechnate(V).

The molecular structures of the two mononuclear title complexes, namely (4-methoxybenzenethiolato-kappaS)oxido[2,2-(3-phenylpropylimino)bis(ethanethiolato)-kappa(3)S,N,S]technetium(V), [Tc(C14H21NS2)(C7H7OS)O], (I), and (4-methoxybenzenethiolato-kappaS)oxido[2,2-(propylimino)bis(ethanethiolato)-kappa(3)S,N,S]technetium(V), [Tc(C7H15NS2)(C7H7OS)O], (II), exhibit the same coordination environment for the central Tc atoms. The atoms are five-coordinated (TcNOS3) with a square-pyramidal geometry comprising a tridentate 2,2-(3-phenylpropylimino)bis(ethanethiolate) or 2,2-(propylimino)bis(ethanethiolate) ligand, a 4-methoxybenzenethiolate ligand and an additional oxide O atom. Intermolecular C-H...O and C-H...S hydrogen bonds between the monomeric units result in two-dimensional layers with a parallel arrangement.