Fully-automated synthesis of 16β-(18)F-fluoro-5α-dihydrotestosterone (FDHT) on the ELIXYS radiosynthesizer.

Noninvasive in vivo imaging of androgen receptor (AR) levels with positron emission tomography (PET) is becoming the primary tool in prostate cancer detection and staging. Of the potential (18)F-labeled PET tracers, (18)F-FDHT has clinically shown to be of highest diagnostic value. We demonstrate the first automated synthesis of (18)F-FDHT by adapting the conventional manual synthesis onto the fully-automated ELIXYS radiosynthesizer. Clinically-relevant amounts of (18)F-FDHT were synthesized on ELIXYS in 90 min with decay-corrected radiochemical yield of 29±5% (n=7). The specific activity was 4.6 Ci/µmol (170 GBq/µmol) at end of formulation with a starting activity of 1.0 Ci (37 GBq). The formulated (18)F-FDHT yielded sufficient activity for multiple patient doses and passed all quality control tests required for routine clinical use

Fully-automated synthesis of 16β-(18)F-fluoro-5α-dihydrotestosterone (FDHT) on the ELIXYS radiosynthesizer.

Noninvasive in vivo imaging of androgen receptor (AR) levels with positron emission tomography (PET) is becoming the primary tool in prostate cancer detection and staging. Of the potential (18)F-labeled PET tracers, (18)F-FDHT has clinically shown to be of highest diagnostic value. We demonstrate the first automated synthesis of (18)F-FDHT by adapting the conventional manual synthesis onto the fully-automated ELIXYS radiosynthesizer. Clinically-relevant amounts of (18)F-FDHT were synthesized on ELIXYS in 90 min with decay-corrected radiochemical yield of 29±5% (n=7). The specific activity was 4.6 Ci/µmol (170 GBq/µmol) at end of formulation with a starting activity of 1.0 Ci (37 GBq). The formulated (18)F-FDHT yielded sufficient activity for multiple patient doses and passed all quality control tests required for routine clinical use

CD38-targeted Immuno-PET of Multiple Myeloma: From Xenograft Models to First-in-Human Imaging

Background: Current measurement of multiple myeloma disease burden are suboptimal. Daratumumab is a monoclonal antibody that targets CD38, an antigen expressed on nearly all myelosna cells. Purpose: To demonstrate preclinical and first-in-human application of an antibody composed of the native daratumumab labeled with the position-emitting radionuclide zirconium 89 (Zr-89) through the chelator deferoxamine (DFO), or Zr-89-DFO-daratumumab , for immunologic PET imaging of multiple myeloma. Materials and Methods: Zr-89-DFO-daratumumab was synthesized by conjugating Zr-89 to daratumumab with DFO. A marine xeno-graft model using CD38-positive OPM2 multiple myeloma cells was used to evaluate CD38-specificity of Zr-89-DFO-daratumumab. Following successful preclinical imaging, a prospective phase I study of 10 patients with multiple myeloma was performed. Study participants received 71 MBq (2 mCi) of intravenous Zr-89-DFO-daratumumab. Each participant underwent four PET/CT scans over the next 8 days, as well as blood chemistry and whole-body counts, to determine safety, tracer biodistribution, pharmacokinetics, and radiation dosimetry. Because( 89)Zr has a half-life of 78 hours, only a single administration of tracer was needed to obtain all four PET/CT scans. Results: Zr-89-DFO-daratumumab was synthesized with radiochemical purity greater than 99%. In the murine model, substantial bone marrow uptake was seen in OPM2 mice but not in healthy mice, consistent with CD38-targeted imaging of OPM2 multiple myeloma cells. In humans,Zr- 89-DFO-daratumumab was safe and demonstrated acceptable dosimetry. Zr-89-DFO-daratumumab uptake was visualized at PET in sites of osseous myeloma. Conclusion: These data demonstrate successful CD38-targeted immunologic PET imaging of multiple myeloma in a murine model and in humans. (C) RSNA, 202

I-124 codrituzumab imaging and biodistribution in patients with hepatocellular carcinoma

Abstract Background I-124 codrituzumab (aka GC33), an antibody directed at Glypican 3, was evaluated in patients with hepatocellular carcinoma (HCC). Fourteen patients with HCC underwent baseline imaging with I-124 codrituzumab (~ 185 MBq, 10 mg). Seven of these patients undergoing sorafenib/immunotherapy with 2.5 or 5 mg/kg of cold codrituzumab had repeat imaging, with co-infusion of I-124 codrituzumab, as part of their immunotherapy treatment. Three patients who progressed while on sorafenib/immunotherapy were re-imaged after a 4-week washout period to assess for the presence of antigen. Serial positron emission tomography (PET) imaging and pharmacokinetics were performed following I-124 codrituzumab. An ELISA assay was used to determine “cold” codrituzumab serum pharmacokinetics and compare it to that of I-124 codrituzumab. Correlation of imaging results was performed with IHC. Short-term safety assessment was also evaluated. Results Thirteen patients had tumor localization on baseline I-124 codrituzumab; heterogeneity in tumor uptake was noted. In three patients undergoing repeat imaging while on immunotherapy/sorafenib, evidence of decreased I-124 codrituzumab uptake was noted. All three patients who underwent imaging after progression while on immunotherapy continued to have I-124 codrituzumab tumor uptake. Pharmacokinetics of I-124 codrituzumab was similar to that of other intact IgG. No significant adverse events were observed related to the I-124 codrituzumab. Conclusions I-124 codrituzumab detected tumor localization in most patients with HCC. Pharmacokinetics was similar to that of other intact iodinated humanized IgG. No visible cross-reactivity with normal organs was observed

Practical considerations for navigating the regulatory landscape of non-clinical studies for clinical translation of radiopharmaceuticals

Abstract Background The development of radiopharmaceuticals requires extensive evaluation before they can be applied in a diagnostic or therapeutic setting in Nuclear Medicine. Chemical, radiochemical, and pharmaceutical parameters must be established and verified to ensure the quality of these novel products. Main body To provide supportive evidence for the expected human in vivo behaviour, particularly related to safety and efficacy, additional tests, often referred to as “non-clinical” or “preclinical” are mandatory. This document is an outcome of a Technical Meeting of the International Atomic Energy Agency. It summarises the considerations necessary for non-clinical studies to accommodate the regulatory requirements for clinical translation of radiopharmaceuticals. These considerations include non-clinical pharmacology, radiation exposure and effects, toxicological studies, pharmacokinetic modelling, and imaging studies. Additionally, standardisation of different specific clinical applications is discussed. Conclusion This document is intended as a guide for radiopharmaceutical scientists, Nuclear Medicine specialists, and regulatory professionals to bring innovative diagnostic and therapeutic radiopharmaceuticals into the clinical evaluation process in a safe and effective way

Additional file 1: of I-124 codrituzumab imaging and biodistribution in patients with hepatocellular carcinoma

Table S1. H score by Ventana method for GPC3 expression. Figure S1. SUVs over normal organs and tissues derived from VOI analysis were divided by SUV in the blood pool at various imaging times. With the exception of the thyroid, which showed increasing accumulation over time and therefore rising tumor-to-blood-pool ratios, activity in other organs had fixed organ-to-blood-pool ratios (spleen and lung) or minimally significantly increased in the liver, kidney, and marrow over time (one-way ANOVA p ≤ 0.05, suggesting that accumulation in those organs was accounted for mainly by the blood pool). Figure S2. Correlation between SUVmax in tumor and soluble GPC3 values measured by GT30/GT607 pair (A) or GT96/M3C11 pair (B). There is a suggestion of some correlation of uptake to sGPC3 values. Figure S3. Pearson correlation between SUVmax in tumor compared to IHC score based on cytoplasm (A) or membrane staining (B). There is a trend to correlation of uptake of antibody expressed in terms of SUV to IHC score. Figure S4. No correlation was observed between SUVmax uptake and various clinical outcomes. (DOCX 300 kb