Microwave-supported preparation of (68)Ga bioconjugates with high specific radioactivity.

The generator-produced positron-emitting (68)Ga (T(1/2) = 68 min) is of potential interest for clinical PET. (68)Ga as a metallic cation is suitable for complexation reactions with chelators, naked or conjugated, with peptides or other macromolecules. Large (68)Ga generator eluate volumes, metal traces from the generator column material, or reaction reagents, however, disturb a fast, reliable, and quantitative labeling procedure. In this paper we describe a simple technique, based on anion exchange, aiming first, to increase the (68)Ga concentration, second to purify it from competing impurities, and third to obtain a fast and quantitative (68)Ga-labeled peptide conjugate that can be applied in humans without further purification. Within 5 min one can obtain from the original 6 mL generator eluate a 200 microL (68)Ga preparation (volume reduction by a factor 30) that is suitable for direct and quantitative labeling of peptide conjugates. DOTATOC (DOTA-D-Phe(1)-Tyr(3)-octreotide, DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was used as a test tracer for comparing the labeling properties of the different (68)Ga preparations. In combination with microwave heating, peptide conjugates of 0.5-1 nmol quantities could be labeled within 10 min with the full (68)Ga activity of a generator. Further purification of the (68)Ga-labeled peptide conjugate was no longer required since the nuclide incorporation was quantitative. The specific radioactivity (with respect to the peptide) was improved by a factor approximately 100 compared to the previously applied techniques using the original generator eluate. The commercial (68)Ge/(68)Ga generator from Obninsk in combination with this system for purification and concentration with an integrated microwave-supported labeling technology resulted in a kitlike technology for (68)Ga-tracer production. The first automated prototype using this technology is being tested.

Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab.

This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5 MBq labelled antibody conjugate (1.11 GBq/mg) 2 days after an intravenous graft of 5.10(6) Daudi cells resulted in tumour-free survival for >120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300 micro g unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%+/-4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%+/-2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with (149)Tb is worthy of consideration as a new-generation radio-immunotherapeutic approach.

The influence of EDTMP-concentration on the biodistribution of radio-lanthanides and 225-Ac in tumor-bearing mice. The ISOLDE Collaboration.

High-resolution gamma spectroscopy was applied to measure simultaneously the biodistribution of carrier-free radionuclides of several lanthanides (141Ce, 145Sm, 149Gd, 167Tm) and 225Ac in tumor-bearing nude mice. Mixtures of the radiotracers were injected in solutions containing different concentrations of EDTMP (ethylenediaminetetramethylenephosphonic acid). The strong dependence of liver uptake on the ionic radius of the radio-lanthanides was confirmed for all tracers used. The ratios of radioactivity concentrated in tumour that concentrated in liver are strongly influenced by the EDTMP concentration, reaching values close to 10 for Tm, 3 for Sm, and 1 for Ac. The optimal EDTMP concentrations, giving highest tumor-to-liver ratios of enrichment, were between 1 and 10 mM for 100 microL injected volume for the animal model used in this experiment. In radionuclide therapy using EDTMP as ligands, close control of ligand concentration will be necessary.

[Scintigraphic use of 87Y during 90Y therapy of bone metastases]. / Szintigraphische Verwendung von 87Y bei der 90Y-Therapie von Knochenmetastasen.

Carrier-free 87Y is produced by cyclotron irradiation of Rb. It decays with a half-life of 80.3 h, transforming via 87mSr to stable 87Sr with the emission of gamma lines of 0.48 and 0.39 MeV. Experience in 6 patients shows good scan quality and correspondence between 99mTc-DPD and 87Y images useful in 90Y-citrate therapy for bone metastases. 87Y offers new possibilities of studying biological kinetics in 90Y therapy. To avoid contamination this should only be used in departments with possibilities of radioactive waste storage and controlled disposal.

Simultaneous study of the biodistribution of radio-yttrium complexed with EDTMP and citrate ligands in tumour-bearing rats.

The influence of the ligands ethylenediaminetetramethylene phosphonic acid (EDTMP) and citrate (CIT) on the biodistribution of radio-yttrium in rats bearing a DS-carcinosarcoma was compared. 88Y-EDTMP and 87Y-CIT were i.v. injected into the same animals. Faster blood clearance and higher renal excretion were observed for the EDTMP-ligand. Of high practical interest is the reduced liver uptake of radio-yttrium (by one order of magnitude) with the EDTMP complex. Since bone and tumour accumulation is only weakly influenced, high tumour-to-liver ratios (up to 14) were observed. We propose to use EDTMP or similar complex ligands for liver blocking when radionuclides like 90Y, 169Yb, 225Ac or other group 3 elements are to be applied in endoradionuclide therapy technique.

A 81Rb/81mKr generator made by ion implantation.

Isotopically pure 81Rb was implanted in plastic foils, and the daughter 81mKr was eluted quantitatively by air or by a 0.9% NaCl solution. The elution yield, the purity of the 81mKr, and the washing-out losses of 81Rb were studied as functions of the implantation density. It was seen that the densities below 5 x 10(12) Rb atoms/cm2 provide a high yield for elution both by liquid and air. The first 100 MBq implantation-type generator was tested by making a lung-ventilation study in man.

Interaction between systemic circulation and brain injuries in newborns.

In several studies different pathogenetic mechanisms of metabolic and/or cardiovascular origin were shown depending on the type of hypoxic or hypoxic/hypercapnic stress and conditions of animals (normal developed or intrauterine growth retarded newborn piglets). Thus, in normal-weight piglets the prevention of compensatory hyperventilation owing to severe hypoxia (artificially ventilated animals) leads to critical, i.e. lethal acidosis. In intrauterine growth retarded piglets, a severe hypoxia cannot be vitally compensated because of the restricted circulatory centralization. Moreover, a limited cerebrovascular dilatation during moderate hypoxia/hypercapnia produces a critical state of the metabolic supply in those animals.

Investigations of cerebral glucose utilization into the newborn brain: a [18F]-FDG positron emission tomography study using a high resolution multiwire proportional chamber detector device.

An experimental approach is presented, where for the first time positron emission tomography (PET, the most important method for in vivo measuring the key functions of brain physiology and metabolism) was applied together with other techniques for quantitative-topological estimation of key parameters such as rCMRGlu in normal and disturbed brain function states in the newborn period.

Temperature course in small volume [18O]water targets for [18F]F- production.

In order to understand the thermal processes occurring within a water target we carried out calculations of heat transfer of the beam energy absorbed from the target water to the target back wall, and compared them with the temperatures measured during irradiations. It was shown, by both the experimental results and the heat transfer calculations, that, at high beam currents, static small volume water targets have a working temperature at the boiling point of the target water. The heat transfer occurs only by movement of the water molecules generated by the boiling target water and not by heat conduction or free convection alone. There is no heat transfer arising from vaporization and reflux.

Stabilities of lanthanide-protein complexes.

After incubation of both serum and HSA solutions with radioactive lanthanide complexes the binding constants of the corresponding lanthanide-protein complexes formed in the protein solutions under physiologic conditions, pH: 7.4, temperature: 310 K, isotonic ionic strength: 0.15 mol/L, were determined. The association constants of the lanthanide-protein complexes formed both in serum and HSA-solutions are equal within the experimental error. In conclusion, serum albumin binding predominates for the radiolanthanides. With the decrease of the ionic radii from 1.034 A (Ce) to 0.858 (Yb) the association constants increased by five orders of magnitude from 1 g Kpr = 4.90 (Ce) to 1 g Kpr = 9.54 (Yb). Further, a serum fractionation with alcohol was carried out to prove that the albumin fraction of serum is responsible for the lanthanide binding in blood.

[Myocardial scintigraphy using omega-I-123 heptadecanoic acid (Rossendorf) in patients with coronary disease]. / Die Myokardszintigraphie mit Omega-123I-Heptadekansäure (Rossendorf) bei Patienten mit koronarer Herzkrankheit.

Scintigraphy using labelled myocardial metabolism precursors makes possible a noninvasive qualitative--and increasingly also quantitative--evaluation of global and regional myocardium, both normally and insufficiently perfused, with normal and disturbed metabolism. Among the labelled precursors, free fatty acids appear as most important, especially the omega-123I-heptadecanoic acid. The experience with the use of this myocardial metabolism precursor in 23 examinations of 11 patients is described.

The influence of isotopic and nonisotopic carriers on the biodistribution and biokinetics of M3+-citrate complexes.

The influence of carrier amounts of Fe, Ga, and Tm on the biodistribution of 67Ga-, 59Fe-, and 167Tm-citrate in mice was investigated. Our results suggest that 167Tm, unlike 67Ga and 59Fe, is not transported by transferrin in the blood. Of the three radioisotopes tested, 167Tm had the highest tumor/background ratio (10 h after the injection). The application of Fe carrier led to an enhancement of the elimination of 67Ga from the blood and muscles, resulting in a better tumor/background ratio.