Jacobus D.M. Herscheid

Evaluation of desferal as a bifunctional chelating agent for labeling antibodies with Zr-89

Zirconium-desferal was prepared and analysed by TLC, NMR and u.v.-spectroscopy. The stoichiometry of the complex was found to be 1:1. Chelation of desferal, coupled to resin, with 88Zr appeared to be fast and almost quantitative in various buffer systems in a broad pH-range (4-7). A high in vitro stability of the zirconium-desferal complex was observed; less than 0.2% zirconium was lost within 24 h in plasma-solutions.

Production of highly pure no-carrier added 89Zr for the labelling of antibodies with a positron emitter

Zr-89 was produced in high amounts (130 mCi/h) via a (p,n) reaction on Y-89. The Zr-89-isotope was purified using a hydroxamate column. More than 95% of the Zr was eluted with 1 mt of 1 M oxalic acid. The radionuclidic purity was over 99.99%. The isolated Zr-89 quantitatively formed complexes with the chelating agent desferal at low concentrations (10-100 mu M).

A facile method for the labeling of proteins with zirconium isotopes

To label proteins with positron emitters with a half-life in the order of days, a method has been developed to label proteins with zirconium (Zr)-isotopes. Therefore, the bifunctional chelating agent desferal (Df) was coupled to albumins via a thioether bond. Labeling of the premodified proteins was easily performed by addition of these proteins to freeze-dried Zr-oxalate. This labeling was efficient (> 90%) and accomplished in several minutes. The conjugates showed a high in vitro stability. Biodistribution studies were performed with 88Zr-citrate, 88Zr-Df, and 88Zr-labeled mouse serum albumin (88Zr-Df-MSA), modified with different amounts of chelating groups. Whereas Zr-citrate was found to accumulate in bone, Zr-Df was cleared very fast by glomerular filtration. The 88Zr-Df-MSA showed similar blood clearance as did 123I-labeled MSA. The biodistribution pattern of 88Zr-Df-MSA differed only from 123I-MSA in that a higher accumulation of Zr in liver, kidney, and spleen was found. The absence of large amounts of 88Zr in bone indicated that in vivo the conjugates are also reasonably stable.

On the stereoselectivity of the reaction of [18F]acetylhypofluorite with glucals☆

Abstract The reaction of acetylhypofluorite with tri-O-acetyl- D -glucal results in products, besides the proposed 2-deoxy-2-fluoro-tetra-O-acetyl- D -glucose, formed by a trans- or a reversed-addition, as analysed by 1H-NMR. Consequently, the resulting end-product FDG (2-deoxy-2-fluoro- D -glucose) is contaminated with 15–20% of the corresponding mannose derivative. Reaction of acetylhypofluorite with D -glucal gives 2-deoxy-2-fluoro- D -mannose (FDM) as the main product, especially when this reaction is performed in acetic acid. A TLC-system was developed to separate FDG and FDM on monosodium-phosphate impregnated silica plates.

A practical method for the preparation of [11C]acetate

For the production of [11C]acetate a simple method is described, which is easy to automate since no solvent extraction or distillation is required. The major step is the trapping of [11C]acetate on a short anion-exchange column after the chloride ions have been removed with a silver column. Organic solvent and radiochemical byproducts such as 11C-acetone and [11C]t-butanol pass this anion-exchange column and are found in the waste. The [11C]acetate is eluted from the column with an injectable citrate buffer. A run requires about 15 min to give [11C]acetate ready for injection in a radiochemical yield of 60–65% and a purity of >99%.

18F-radiopharmacokinetics of [18F]-5-fluorouracil in a mouse bearing two Colon tumors with a different 5-fluorouracil sensitivity: A study for a correlation with oncological results

The tissue distribution and biodynamics of 18F-labelled 5-fluorouracil (FU) are described and studied for correlation with its in vivo antitumor activity. The in vivo model consisted of Balb/c mice bearing a FU sensitive (Colon 26-10 carcinoma) tumor in the left and a less responsive (Colon 26 carcinoma) tumor in the right abdominal side of the animal. Distribution and efflux of 18F-label from tumor, blood, and other tissues were determined by obduction at 0.5, 1, 2, 4, and 6 h postintravenous injection. For a comparison, the 18F-labeled 5-fluoro-6-hydroxy and cis-5-fluoro-6-ethoxy uracil adducts were studied in the same in vivo model. For 18F-FU it was found that the 18F-label tumor kinetics rapidly fell into a biphasic mode: a relatively short 18F beta phase (18F t1/2 beta 21 +/- 3 min), linked with the total body metabolic capacity and clearance of the animal, and a longer 18F gamma phase, linked with the intrinsic intratumoral FU metabolism (Colon 26-10: 18F t1/2 gamma 10.3 h; Colon 26: 18F t1/2 gamma 5.6 h). It is proposed that the observed faster 18F efflux of the less responsive Colon 26 corresponds to an enhanced breakdown of 5-fluoronucleotides to 5-fluoronucleosides and subsequent elimination from the tumor cells. It is concluded that on PET scanning, measurement of the dynamic 18F t1/2 gamma and 18F t1/2 beta parameter is of prime importance for an insight in the in vivo tumor biology of a patient.

Tissue distribution of [18F]-5-fluorouracil in mice: effects of route of administration, strain, tumour and dose

SummaryIn a study investigating the usefulness of 5-fluorouracil labelled with fluorine 18 ([18F]-5-FU) in cancer chemotherapy, the tissue distribution of the radiolabel was determined in mice at 2, 4 and 6 h after administration by varying several parameters such as the mode of administration, the strain of mouse, the presence of a tumour and the total dose of 5-FU. The tissue distribution of fluorine 18 after i. p. injection pointed to an altered behaviour of the drug and/or its metabolites when compared with values obtained after i.v. injection, but no difference was found in the accumulation of radiolabel in the tumour. A comparison of non-tumour-bearing BALB/c and C57Bl/6 mice revealed that the latter showed a higher radiolabel accumulation of the drug and its metabolites in the liver, kidney, intestines and coecum (P <0.05 at 2 and 4 h). In tumour-bearing mice, especially at 2 h, the tissue accumulation of radiolabel was found to be significantly higher than in non-tumour-bearing controls (in BALB/c mice bearing colon 26 carcinoma,P <0.05 for all tissues; in C57Bl/6 mice bearing colon 38 carcinoma,P <0.05 for the blood, lung, liver, kidney, large intestines, coecum and muscle). Finally, a comparison of injections of a tracer dose of [18F]-5-FU (2.5 mg/kg) vs a therapeutic dose (100 mg/kg) revealed only small differences in the accumulation of fluorine 18 in the liver and kidney.

Manganese-52m for direct application: A new 52Fe/52mMn generator based on a hydroxamate resin

A new generator system has been developed using the 52Fe/52mMn parent-daughter pair. A polymeric hydroxamate resin is used for the fixation of 52Fe, and the short-lived positron-emitter 52mMn is eluted in physiological saline. Preliminary animal studies in rats gave similar results with respect to biodistribution as are obtained for [54Mn] manganous chloride.

N-succinyldesferrioxamine B: a potential radiopharmaceutical for assessing renal function

N-Succinyldesferrioxamine B was found to be cleared very fast by the kidneys. Since this compound can strongly chelate several metals, including the generator-produced isotopes 113mIn and 68Ga, 67Ga-N-succinyldesferrioxamine B (SDF) was tested as a substitute for 131I-o-iodohippuric acid (OIH) in the measurement of renal tubular secretion. In rats both compounds showed similar biodistribution patterns with a greater excretion rate of SDF. In rabbits, however, the excretion rate of OIH was superior to that of SDF. Inhibition of tubular secretion by probenecid was nearly ineffective in the renal clearance of both OIH and SDF.

A simplified synthesis of 18F-labelled cytosine- and uracil-nucleosides

Abstract 18 F-labelled cytosine- and uracil- nucleosides are synthesized starting from their unprotected parent nucleosides by reaction with acetylhypofluorite in acetic acid in an overall radiochemical yield of 20 and 30% respectively.