Synthesis and evaluation of radioiodinated estrogens for diagnosis and therapy of male urogenital tumours.

The preparation of 24 estrogens, their estrogen receptor (ER) affinity and studies of radioiodinated estrogen binding to ER-positive male bladder tumor cells (HTB9) are described. The estrogens with the highest affinity were selected using fluorescence anisotropy assays. A 2,2,2-trifluoroethyl group at the 11ß-position caused particularly promising affinity. (Radio)iodination was performed on the 17α-vinyl group. Binding studies on HTB9 cells revealed picomolar affinities of radioconjugates 19 and 31, indicating promising ability for targeting of urogenital tumors.

Translational Development of a Zr-89-Labeled Inhibitor of Prostate-specific Membrane Antigen for PET Imaging in Prostate Cancer.

PURPOSE: We present here a Zr-89-labeled inhibitor of prostate-specific membrane antigen (PSMA) as a complement to the already established F-18- or Ga-68-ligands. PROCEDURES: The precursor PSMA-DFO (ABX) was used for Zr-89-labeling. This is not an antibody, but a peptide analogue of the precursor for the production of [177Lu]Lu-PSMA-617. The ligand [89Zr]Zr-PSMA-DFO was compared with [68Ga]Ga-PSMA-11 and [18F]F-JK-PSMA-7 in vitro by determination of the Kd value, cellular uptake, internalization in LNCaP cells, biodistribution studies with LNCaP prostate tumor xenografts in mice, and in vivo by small-animal PET imaging in LNCaP tumor mouse models. A first-in-human PET was performed with [89Zr]Zr-PSMA-DFO on a patient presenting with a biochemical recurrence after brachytherapy and an ambiguous intraprostatic finding with [18F]F-JK-PSMA-7 but histologically benign cells in a prostate biopsy 7 months previously. RESULTS: [89Zr]Zr-PSMA-DFO was prepared with a radiochemical purity ≥ 99.9% and a very high in vitro stability for up to 7 days at 37 °C. All radiotracers showed similar specific cellular binding and internalization, in vitro and comparable tumor uptake in biodistribution experiments during the first 5 h. The [89Zr]Zr-PSMA-DFO achieved significantly higher tumor/background ratios in LNCaP tumor xenografts (tumor/blood: 309 ± 89, tumor/muscle: 450 ± 38) after 24 h than [68Ga]Ga-PSMA-11 (tumor/blood: 112 ± 57, tumor/muscle: 58 ± 36) or [18F]F-JK-PSMA-7 (tumor/blood: 175 ± 30, tumor/muscle: 114 ± 14) after 4 h (p < 0.01). Small-animal PET imaging demonstrated in vivo that tumor visualization with [89Zr]Zr-PSMA-DFO is comparable to [68Ga]Ga-PSMA-11 or [18F]F-JK-PSMA-7 at early time points (1 h p.i.) and that PET scans up to 48 h p.i. clearly visualized the tumor at late time points. A late [89Zr]Zr-PSMA-DFO PET scan on a patient with biochemical recurrence (BCR) had demonstrated intensive tracer accumulation in the right (SUVmax 13.25, 48 h p.i.) and in the left prostate lobe (SUV max 9.47), a repeat biopsy revealed cancer cells on both sides. CONCLUSION: [89Zr]Zr-PSMA-DFO is a promising PSMA PET tracer for detection of tumor areas with lower PSMA expression and thus warrants further clinical evaluation.

Stability of radioactive colloids for radiation synovectomy: influence of X-ray contrast agents, anaesthetics and glucocorticoids in vitro.

AIM: This in-vitro study investigated the influence of the contrast agents iothalamate (Conray) and special preparations of iotrolan (Isovist) and iopromide (Ultravist) without ethylenediaminetetraacetic acid (EDTA), the anaesthetic Scandicain and the glucocorticoid triamcinolone on the stability of 90Y-, 169Er- and 186Re-radiocolloids used for radiation synovectomy. METHODS: Vials of 1 ml of synovial fluid and 0.02 ml of radiocolloid suspension (0.56-3.6 MBq) were mixed with 0.06, 0.6 and 1.0 ml of each contrast agent. In an additional series, 0.1 ml of Scandicain and 0.1 ml of triamcinolone were tested. Thin layer chromatography and ultrafiltration/centrifugation were performed between 1 h and 15 days after incubation with negative and positive controls. RESULTS: Within 24 h, 0.6 and 1.0 ml of Conray had mobilized 5-20% of the 90Y and 169Er out of the colloids. No interference between 186Re-colloids and Conray was visible before the ninth day after incubation. Iotrolan and iopromide without EDTA had no effect on the stability at shorter incubation periods of up to 6 days. The addition of Scandicain did not produce low-molecular 90Y or 169Er in the presence of synovial fluid. The fraction of low-molecular 186Re reached 4% after 24 h. Triamcinolone did not have any effect on stability in the presence of synovial fluid. CONCLUSION: The disintegration of the radioactive colloids can be attributed to either the formation of EDTA complexes or radiolytic effects. The volume of the injected contrast agent should be as small as possible to confirm correct intra-articular distribution.

Characterization of SnO2-based (68)Ge/ (68)Ga generators and (68)Ga-DOTATATE preparations: radionuclide purity, radiochemical yield and long-term constancy.

BACKGROUND: With the increasing utilization of (68)Ge-(68)Ga radionuclide generators, (68)Ga labelled peptides like DOTATATE are receiving more attention in nuclear medicine. On the one hand, the long half-life of the parent nuclide (68)Ge is an enormous advantage for routine applications, but the question of the long-term stability of the (68)Ge breakthrough arises, which up to now has scarcely been investigated. METHOD: A sum of 123 eluates from four different (68)Ge-(68)Ga generators (iThemba Labs, Faure, South Africa) and 115 samples of the prepared radiopharmaceutical (68)Ga-DOTATATE were measured first with a dose calibrator and again after decay of the eluted (68)Ga via gamma-ray spectrometry. A complete decay curve was recorded for one sample eluate. A further three eluates were eluted in ten fractions of 0.5 ml in order to obtain detailed information concerning the distribution of the two nuclides within the eluates. The influences of factors such as the amount of DOTATATE, addition of Fe(3+) salts and replacement of HEPES buffer with sodium acetate on the radiochemical synthesis were also tested. RESULTS: The content of long-lived (68)Ge breakthrough increases over the entire period of use to more than 100 ppm. The labelling process with the chelator DOTA removes (68)Ge efficiently. The maximum activity found in the residues of the radiopharmaceuticals investigated in this study was below 10 Bq in nearly all cases. In many cases (12% of the labelled substance), the long-lived parent nuclide could not be identified at all. The labelling process is still viable for reduced amounts of the chelator and with acetate buffer. CONCLUSION: Effective doses received by the patient from (68)Ge in the injected radiopharmaceutical (68)Ga-DOTATATE are lower than 0.1 µSv and are therefore practically negligible, especially when compared with the contribution of the PET radiopharmaceutical itself. Gamma-ray spectrometry as recommended by the European Pharmacopeia is suitable for quantification of radionuclidic impurities.