Cyclotron production and cyclometallation chemistry of 192Ir

Introduction To explore new questions and techniques in nuclear medicine, new isotopes with novel chemical and nuclear properties must be developed. We are interested in the small cyclotron production of new radiometals for the development of new radiopharmaceuticals (RX). In an example of RX multifunctionality, Luminescence Cell Imaging (LCI) has been combined with radio-isotopes to allow compounds that can be imaged with both optical microscopy and nuclear techniques [1]. Within this field, iridium cy-clometalates have good potential with excellent photophysical properties [2]. As well, low specific activity iridium-192 has found use in brachy-therapy as a high-intensity beta emitter [3]. Despite this, iridium radioisotopes have yet to be applied to cyclometalation chemistry, or a radiochemical isolation method developed for carrier free production on a medical cyclotron. Our goal is to demonstrate the feasibility of the production and isolation of radio-iridium, and its application to cyclometalate chemistry as a potentially interesting tool for nuclear medicine research. Materials and Methods Following literature precedent [4], natural osmium was electroplated onto a silver disc from basic media containing osmium tetroxide and sulphamic acid. The thin deposits obtained (15–20 mg cm−2) were weighed and characterized with scanning electron microscopy. Targets were irradiated using the TRIUMF TR13 cyclotron, delivering 12.5 MeV protons to the target disc. Initial bombardments were per-formed at 5 μA; gamma spectra of the targets were collected 24 hours after end of bombardment. The irradiated material was oxidized, dissolved from the target backing, and separated via anion exchange. In parallel to the isotope production work, non-radioactive iridium was used to define a chemical procedure suitable for the synthesis of model iridium cyclometalate compounds given low concentrations of radioiridium. These experiments will be performed with radioactive iridium in the next step of the research project. Results and Conclusion Proton bombardment of natural osmium yielded a range of iridium isotopes, with characteristic spectral lines corresponding to 186-190Ir, and 192Ir; no other characteristic radiation was observed. The EOB activity of each isotope was then used in thin target calculations to approximate their (p,n) cross section. Preliminary cross section measurements of the 192Os(p,n)192Ir reaction (53 ± 13 mb @ 12.5 MeV) confirm published data (52.3 ± 5.7 mb @ 12.2 MeV) [6], and provide as-yet unpublished data on the lower mass number isotopes. The progress of radioactive iridium through the radiochemical separation was tracked with a dose calibrator; the osmium complex formed was brightly coloured and could be seen retained on the column. The overall efficiency of the process is estimated at 80 %. Radioactive cyclometallation chemistry is currently under-way. The production and isolation of a range of iridium isotopes in a chemically useful form was demonstrated, and is ready to be applied to a cyclometalate model compound. Future work will investigate the production of 192Ir from enriched 192Os

Production of radiometals in a liquid target

Introduction Access to radiometals suitable for labeling novel molecular imaging agents requires that they be routinely available and inexpensive to obtain. Proximity to a cyclotron center outfitted with solid target hardware, or to an isotope generator for a radiometal of interest is necessary, both of which can be significant hurdles in availability of less common isotopes. Herein, we describe the production of 44Sc, 68Ga, 89Zr, 86Y and 94mTc in a solution target which allows for the production of various radiometallic isotopes, enabling rapid isotope-biomolecule pairing optimization for tracer development. Work on solution targets has also been performed by other groups [e.g. 1, 2]. Material and Methods Solutions containing a high concentration of natural-abundance zinc nitrate, yttrium nitrate, calcium nitrate [3], strontium nitrate or ammonium heptamolybdate [4] were irradiated on a 13 MeV cyclotron using a standard liquid target. Some of the solutions contained additional hydrogen peroxide or nitric acid to improve solubility and reduce pressure rise in the target during irradiation. Yields calculated using theoretical cross sections (EMPIRE [5]) were compared to the measured yields. In addition, we tested a thermo-syphon target design for the production of 44Sc. Chemical separation of the product from the target material was carried out on a remote apparatus modeled after that of Siikanen [6]. Results and Conclusion The proposed approach enabled the production of quantities sufficient for chemical or biological studies for all metals discussed. In the case of 68Ga, activity up to 480 ± 22 MBq was obtained from a one hour run with a beam current of 7 µA, potentially enabling larger scale clinical production. Considering all reactions, the ratio of theoretical saturation yields to experimental yields ranges from 0.8 for 94mTc to 4.4 for 44Sc. The thermo-syphon target exhibited an increase of current on the target by a factor of 2.5 and an increase in yield by a factor of five for the production of 44Sc. Separation methods were developed for all isotopes and separation efficiency ranges from 71 ± 1 % for 94mTc to 99 ± 4 % for 86Y. 44Sc, 68Ga, and 86Y were successfully used in labeling studies with a model 1,4,7,10-tetrazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelate, while 89Zr coordination behavior was tested using desferrioxamine-alkyne (DFO-alkyne). In summary, we present a promising new method to produce a suite of radiometals in a liquid target. Future work will continue to expand the list of radiometals and to apply this approach to the development of various peptide, protein and antibody radiotracers

Second trimester inflammatory and metabolic markers in women delivering preterm with and without preeclampsia.

ObjectiveInflammatory and metabolic pathways are implicated in preterm birth and preeclampsia. However, studies rarely compare second trimester inflammatory and metabolic markers between women who deliver preterm with and without preeclampsia.Study designA sample of 129 women (43 with preeclampsia) with preterm delivery was obtained from an existing population-based birth cohort. Banked second trimester serum samples were assayed for 267 inflammatory and metabolic markers. Backwards-stepwise logistic regression models were used to calculate odds ratios.ResultsHigher 5-α-pregnan-3β,20α-diol disulfate, and lower 1-linoleoylglycerophosphoethanolamine and octadecanedioate, predicted increased odds of preeclampsia.ConclusionsAmong women with preterm births, those who developed preeclampsia differed with respect metabolic markers. These findings point to potential etiologic underpinnings for preeclampsia as a precursor to preterm birth

River histories : A thematic review

Peer reviewe

High power targets for cyclotron production of 99mTc‡

Introduction Technetium-99m, supplied in the form of 99Mo/99mTc generators, is the most widely used radioisotope for nuclear medical imaging. The parent isotope 99Mo is currently produced in nuclear reactors. Recent disruptions in the 99Mo supply chain [1] prompted the development of methods for the direct accelerator-based production of 99mTc. Our approach involves the 100Mo(p,2n)99mTc reaction on isotopically enriched molybdenum using small medical cyclotrons (Ep ≤ 20 MeV), which is a viable method for the production of clinically useful quantities of 99mTc [2]. Multi-Curie production of 99mTc requires a 100Mo target capable of dissipating high beam intensities [3]. We have reported the fabrication of 100Mo targets of both small and large area tar-gets by electrophoretic deposition and subsequent sintering [4]. As part of our efforts to further enhance the performance of molybdenum targets at high beam currents, we have developed a novel target system (initially de-signed for the GE PETtrace cyclotron) based on a pressed and sintered 100Mo plate brazed onto a dispersion-strengthened copper backing. Materials and Methods In the first step, a molybdenum plate is produced similarly to the method described in [5] by compacting approximately 1.5 g of commercially available 100Mo powder using a cylindrical tool of 20 mm diameter. A pressure between 25 kN/cm2 and 250 kN/cm2 is applied by means of a hydraulic press. The pressed molybdenum plate is then sintered in a reducing atmosphere (Ar/2% H2) at 1,700 oC for five hours. The resulting 100Mo plates have about 90–95 % of the molybdenum bulk density. The 100Mo plate is furnace brazed at ~750 oC onto a backing manufactured from a disperse on strengthened copper composite (e.g. Glidcop AL-15) using a high temperature silver-copper brazing filler. This process yields a unique, mechanically and thermally robust target system for high beam power irradiation. Irradiations were performed on the GE PETtrace cyclotrons at LHRI and CPDC with 16.5 MeV protons and beam currents ≥ 100 µA. Targets were visually inspected after a 6 hour, 130 µA bombardment (2.73 kW/cm2, average) and were found fully intact. Up to 4.7 Ci of 99mTc have been produced to date. The saturated production yield remained constant between 2 hour and 6 hour irradiations. Results and Conclusion These results demonstrate that our brazed tar-get assembly can withstand high beam intensities for long irradiations without deterioration. Efforts are currently underway to determine maximum performance parameters

Extending the scope of pooled analyses of individual patient biomarker data from heterogeneous laboratory platforms and cohorts using merging algorithms

Background: A common challenge in medicine, exemplified in the analysis of biomarker data, is that large studies are needed for sufficient statistical power. Often, this may only be achievable by aggregating multiple cohorts. However, different studies may use disparate platforms for laboratory analysis, which can hinder merging. Methods: Using circulating placental growth factor (PIGF), a potential biomarker for hypertensive disorders of pregnancy (HDP) such as preeclampsia, as an example, we investigated how such issues can be overcome by inter-platform standardization and merging algorithms. We studied 16,462 pregnancies from 22 study cohorts. PIGF measurements (gestational age >= 20 weeks) analyzed on one of four platforms: R & Systems, Alere (R) Triage, Roche (R) Elecsys or Abbott (R) Architect, were available for 13,429 women. Two merging algorithms, using Z-Score and Multiple of Median transformations, were applied. Results: Best reference curves (BRC), based on merged, transformed PIGF measurements in uncomplicated pregnancy across six gestational age groups, were estimated. Identification of HDP by these PIGF-BRCS was compared to that of platform-specific curves. Conclusions: We demonstrate the feasibility of merging PIGF concentrations from different analytical platforms. Overall BRC identification of HDP performed at least as well as platform-specific curves. Our method can be extended to any set of biomarkers obtained from different laboratory platforms in any field. Merged biomarker data from multiple studies will improve statistical power and enlarge our understanding of the pathophysiology and management of medical syndromes. (C) 2015 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.Peer reviewe

Pre-exenterative chemotherapy, a novel therapeutic approach for patients with persistent or recurrent cervical cancer

BACKGROUND: Most cervical cancer patients with pelvic recurrent or persistent disease are not candidates for exenteration, therefore, they only receive palliative chemotherapy. Here we report the results of a novel treatment modality for these patients pre-exenterative chemotherapy- under the rational that the shrinking of the pelvic tumor would allow its resection. METHODS: Patients with recurrent or persistent disease and no evidence of systemic disease, considered not be candidates for pelvic exenteration because of the extent of pelvic tumor, received 3-courses of platinum-based chemotherapy. Response was evaluated by CT scan and bimanual pelvic examination; however the decision to perform exenteration relied on the physical findings. Toxicity to chemotherapy was evaluated with standard criteria. Survival was analyzed with the Kaplan-Meier method. RESULTS: Seventeen patients were studied. The median number of chemotherapy courses was 4. There were 9 patients who responded to chemotherapy, evaluated by bimanual examination and underwent pelvic exenteration. Four of them had pathological complete response. Eight patients did not respond and were not subjected to surgery. One patient died due to exenteration complications. At a median follow-up of 11 months, the median survival for the whole group was 11 months, 3 months in the non-operated and 32 months in those subjected to exenteration. CONCLUSION: Pre-exenterative chemotherapy is an alternative for cervical cancer patients that are no candidates for exenteration because of the extent of the pelvic disease. Its place in the management of recurrent disease needs to be investigated in randomized studies, however, its value for offering long-term survival in some of these patients with no other option than palliative care must be stressed