Biological behavior of a new 68Ga-labelled glucose derivative as a potential agent for tumor imaging

Glucose analogs and derivatives labeled with positron emitter 68Ga are considered to be a promising alternative to widely used radiotracer 18F-FDG for tumor PET imaging. In this study a biodistribution of a new glucose derivative labeled with 68Ga (68Ga-NODA-thioglucose) was investigated. All biodistribution studies were carried out in Balb/c mice with experimental model of tumor or aseptic inflammation. The tumor uptake of 68Ga-NODA-TG decreased throughout the study from 3.00±0.08 % ID/g to 1.06±0.04 %ID/g. The peak amount of 68Ga-NODA-TG in muscle with inflammation reached 4.33±0.12 % ID/g, decreasing to 0.23±0.08 % ID/g. In other organs and tissues the biodistribution of 68Ga-NODA-TG was similar in tumor-bearing mice and mice with aseptic inflammation. In conclusion, the obtained results suggest that 68Ga-NODA-TG has the potential for clinical application as a PET tracer.

The Use of a Non-Conventional Long-Lived Gallium Radioisotope 66Ga Improves Imaging Contrast of EGFR Expression in Malignant Tumours Using DFO-ZEGFR:2377 Affibody Molecule

Epidermal growth factor receptor (EGFR) is overexpressed in many malignancies. EGFR-targeted therapy extends survival of patients with disseminated cancers. Radionuclide molecular imaging of EGFR expression would make EGFR-directed treatment more personalized and therefore more efficient. A previous study demonstrated that affibody molecule [68Ga]Ga-DFO-ZEGFR:2377 permits specific positron-emission tomography (PET) imaging of EGFR expression in xenografts at 3 h after injection. We anticipated that imaging at 24 h after injection would provide higher contrast, but this is prevented by the short half-life of 68Ga (67.6 min). Here, we therefore tested the hypothesis that the use of the non-conventional long-lived positron emitter 66Ga (T1/2 = 9.49 h, β+ = 56.5%) would permit imaging with higher contrast. 66Ga was produced by the 66Zn(p,n)66Ga nuclear reaction and DFO-ZEGFR:2377 was efficiently labelled with 66Ga with preserved binding specificity in vitro and in vivo. At 24 h after injection, [66Ga]Ga-DFO-ZEGFR:2377 provided 3.9-fold higher tumor-to-blood ratio and 2.3-fold higher tumor-to-liver ratio than [68Ga]Ga-DFO-ZEGFR:2377 at 3 h after injection. At the same time point, [66Ga]Ga-DFO-ZEGFR:2377 provided 1.8-fold higher tumor-to-blood ratio, 3-fold higher tumor-to-liver ratio, 1.9-fold higher tumor-to-muscle ratio and 2.3-fold higher tumor-to-bone ratio than [89Zr]Zr-DFO-ZEGFR:2377. Biodistribution data were confirmed by whole body PET combined with magnetic resonance imaging (PET/MRI). The use of the positron emitter 66Ga for labelling of DFO-ZEGFR:2377 permits PET imaging of EGFR expression at 24 h after injection and improves imaging contrast.

Accurate determination of production data of the non-standard positron emitter 86Y via the 86Sr(p,n)-reaction

In view of several significant discrepancies in the excitation function of the 86Sr(p,n)86g+xmY reaction which is the method of choice for the production of the non-standard positron emitter 86Y for theranostic application, we carried out a careful measurement of the cross sections of this reaction from its threshold up to 16.2 MeV at Forschungszentrum Jülich (FZJ) and from 14.3 to 24.5 MeV at LBNL. Thin samples of 96.4% enriched 86SrCO3 were prepared by sedimentation and, after irradiation with protons in a stacked-form, the induced radioactivity was measured by high-resolution γ-ray spectrometry. The projectile flux was determined by using the monitor reactions natCu(p,xn)62,63,65Zn and natTi(p,x)48V, and the calculated proton energy for each sample was verified by considering the ratios of two reaction products of different thresholds. The experimental cross section data obtained agreed well with the results of a nuclear model calculation based on the code TALYS. From the cross section data, the integral yield of 86Y was calculated. Over the optimum production energy range Ep = 14 → 7 MeV the yield of 86Y amounts to 291 MBq/μA for 1 h irradiation time. This value is appreciably lower than the previous literature values calculated from measured and evaluated excitation functions. It is, however, more compatible with the experimental yields of 86Y obtained in clinical scale production runs. The levels of the isotopic impurities 87mY, 87gY, and 88Y were also estimated and found to be <2% in sum.

Hybrid Multimodal Imaging Synthons for Chemoselective and Efficient Biomolecule Modification with Chelator and Near-Infrared Fluorescent Cyanine Dye

The development of hybrid multimodal imaging synthons (MIS), carrying in addition to a chelator for radiometal labeling also a near-infrared (NIR) fluorescent cyanine dye was the aim of this work. The MIS should be introducible into biomolecules of choice via an efficient and chemoselective click chemistry reaction. After chemical optimization, a successful synthetic strategy towards such hybrid MIS was developed, based on solid phase-based synthesis techniques and applying different near-infrared fluorescent cyanine dyes. The developed hybrid agents were shown to be easily introducible into a model homobivalent peptidic gastrin-releasing peptide receptor- (GRPR)-specific carrier without forming any side products and the MIS as well as their bioconjugates were radiolabeled with the positron-emitter 68Ga3+. The hybrid multimodal agents were characterized with regard to their logDs, GRPR target affinities and photophysical characteristics. It could be shown that the properties of the bioconjugates were not per se affected by the introduction of the MIS but that the cyanine dye used and specifically the number of comprised negative charges per dye molecule can have a considerable influence on target receptor binding. Thus, the molecular toolbox described here enables the synthesis of tailored hybrid multimodal imaging synthons for biomolecule modification, meeting the specific need and envisioned application of the combined imaging agent.

Cross-section measurements and production of 72Se with medium to high energy protons using arsenic containing targets

Experiments were performed to evaluate production of 72Se, parent radionuclide of the positron emitter 72As, at high energy at the Brookhaven Linac Isotope Producer (BLIP). Excitation functions for 75As(p, xn)72/75Se in the 52-105 MeV energy range were measured by irradiating thin gallium arsenide (GaAs) wafers. Maximum cross section value for the natAs(p, 4n)72Se reaction in the energy range was 103±9 mb at 52±1 MeV. Production size GaAs and arsenic metal (As°) targets were irradiated with 136 μA and 165 μA beam current possessing an initial Linac energy of 117 MeV. A total of 3.77±0.1 GBq (102±3 mCi) of 72Se was produced from a GaAs target at a calculated target entrance energy of 105.4 MeV, and 13.8±0.3 GBq (373±8 mCi) of 72Se from an As° target at a calculated incident energy of 49.5 MeV irradiated for 116.5 h and 68.9 h, respectively.