Continued Availability of the Tungsten-188/Rhenium-188 Generator to Enhance Therapeutic Utility of 188Re

Rhenium-188 (188Re) is a high energy beta-emitting radioisotope of widespread interest for use in nuclear medicine, oncology and other therapeutic applications. High energy beta emission (16.9 hour half-life) with Emax 2.12 MeV and gamma emission at 155 keV (15 %) are key factors for effective therapy and imaging for tissue kinetics and dosimetry evaluation. Moreover, on-demand availability of 188Re in a highly reproducible manner from the 188W/188Re generator system is an important capability for installation in a hospital-based or a central radiopharmacy for cost effective availability of no-carrier-added (NCA) 188Re. Because of the long 69.7 day half-life of the188W generator parent, the use of well-established post 188Re elution specific volume concentration technology allow generators to have a useful/predictable operational shelf-life of a few months. This paper provides a holistic review of the development, availability and use of the 188W/188Re generator prototypes

Important Clinical Applications of 188Rhenium for Radionuclide Therapy

Although established clinical utility is of key importance in choosing agents for radionuclide therapy, other key factors include costs and GMP availability of sterile, pyrogen-free, regulatory approved radiopharmaceuticals. No-carrier-added (NCA) 188Rhenium(188Re, 16.9 hour half-life; 155 keV gamma emission) is available on demand as 188Re-perrhenate from saline elution of a 188Tungsten/188Rhenium(188W/188Re) generator. The availability and superb radionuclidic and chemical properties make 188Re an excellent candidate for radionuclide therapy. This radioisotope is readily attached to a variety of targeting agents and also emits high energy beta particles (Emax 2.12 MeV) for therapy. Over the last 30 years the effectiveness of 188Re for a variety of therapeutic applications has been established in multiple clinical studies. This overview provides a brief summary of clinical applications with 188Re-labeled agents as an introduction to the detailed clinical discussions in the following papers. Although 188Re-labeled radiopharmaceuticals for routine clinical use and accompanying reimbursement are not yet commercially available, several agents have been evaluated in clinical studies. In addition, a large number of 188Re radiopharmaceutical agents have been developed and evaluated in pre-clinical studies over the last three decades. This review focuses on providing examples of 188Re-labeled radiopharmaceutical agents which have entered late stage clinical use and have demonstrated good efficacy. These key applications include palliative treatment of skeletal metastases, intra-arterial therapy of liver cancer and post PTCA intravascular inhibition of arterial restenosis. Also, 188Re radiopharmaceuticals had been developed and initially assessed for synovectomy and for marrow suppression. More recently, a unique device-based technology has entered clinical use for therapy of non-melanoma skin cancer using a 188Re topical cream. Finally, 188Re-antibodies are being developed for the potential therapy of infectious disease and this unique new therapeutic strategy is expected to enter clinical trials in the near future

Production of Medical Radioisotopes with High Specific Activity in Photonuclear Reactions with γ\gamma Beams of High Intensity and Large Brilliance

We study the production of radioisotopes for nuclear medicine in $(\gamma,x{\rm n}+y{\rm p})$ photonuclear reactions or ($\gamma,\gamma'$) photoexcitation reactions with high flux [($10^{13}-10^{15}$)$\gamma$/s], small diameter $\sim (100 \, \mu$m$)^2$ and small band width ($\Delta E/E \approx 10^{-3}-10^{-4}$) $\gamma$ beams produced by Compton back-scattering of laser light from relativistic brilliant electron beams. We compare them to (ion,$x$n$+ y$p) reactions with (ion=p,d,$\alpha$) from particle accelerators like cyclotrons and (n,$\gamma$) or (n,f) reactions from nuclear reactors. For photonuclear reactions with a narrow $\gamma$ beam the energy deposition in the target can be managed by using a stack of thin target foils or wires, hence avoiding direct stopping of the Compton and pair electrons (positrons). $(\gamma,\gamma')$ isomer production via specially selected $\gamma$ cascades allows to produce high specific activity in multiple excitations, where no back-pumping of the isomer to the ground state occurs. We discuss in detail many specific radioisotopes for diagnostics and therapy applications. Photonuclear reactions with $\gamma$ beams allow to produce certain radioisotopes, e.g. $^{47}$Sc, $^{44}$Ti, $^{67}$Cu, $^{103}$Pd, $^{117m}$Sn, $^{169}$Er, $^{195m}$Pt or $^{225}$Ac, with higher specific activity and/or more economically than with classical methods. This will open the way for completely new clinical applications of radioisotopes. For example $^{195m}$Pt could be used to verify the patient's response to chemotherapy with platinum compounds before a complete treatment is performed. Also innovative isotopes like $^{47}$Sc, $^{67}$Cu and $^{225}$Ac could be produced for the first time in sufficient quantities for large-scale application in targeted radionuclide therapy.Comment: submitted to Appl. Phys.

Pion photoproduction on the nucleon in the quark model

We present a detailed quark-model study of pion photoproduction within the effective Lagrangian approach. Cross sections and single-polarization observables are investigated for the four charge channels, $\gamma p\to \pi^+ n$, $\gamma n\to \pi^- p$, $\gamma p\to \pi^0 p$, and $\gamma n\to \pi^0 n$. Leaving the $\pi N\Delta$ coupling strength to be a free parameter, we obtain a reasonably consistent description of these four channels from threshold to the first resonance region. Within this effective Lagrangian approach, strongly constrainted by the quark model, we consider the issue of double-counting which may occur if additional {\it t}-channel contributions are included.Comment: Revtex, 35 pages, 16 eps figures; version to appear on PR

Development and Evaluation of Rhenium-188-labeled Radioactive Stents for Restenosis Therapy and Development of Strategies for Radiolabeling Brachytherapy Sources with Palladium-103

This project involved collaboration between InnerDyne, Inc., and radiopharmaceutical research programs at the Oak Ridge National Laboratory (ORNL) and Brookhaven National Laboratory (BNL) which explored new strategies for the development and animal testing of radioactive rhenium-188-labeled implantable stent sources for the treatment of coronary restenosis after angioplasty and the development of chemical species radiolabeled with the palladium-103 radioisotope for the treatment of cancer. Rhenium-188 was made available for these studies from radioactive decay of tungsten-188 produced in the ORNL High Flux Isotope Reactor (HFIR). Stent activation and coating technology was developed and provided by InnerDyne, Inc., and stent radiolabeling technology and animal studies were conducted by InnerDyne staff in conjunction with investigators at BNL. Collaborative studies in animals were supported at sites by InnerDyne, Inc. New chemical methods for attaching the palladium-103 radioisotope to bifunctional chelate technologies were developed by investigators at ORNL

Use of Reactor-Produced Radioisotopes for Prevention Restenosis After Angioplasty

Coronary heart disease leads to myocardial infarction and is a major cause of death in the US. Myocardial infarctions result from atherosclerotic plaque deposits in the coronary arteries, reducing blood flow through these arteries which supply oxygen and nutrients to the heart muscle. The two major approaches for restoring adequate blood flow are coronary bypass graft surgery and coronary angioplasty. Angioplasty is a routinely used clinical procedure, where a deflated balloon attached to the end of a long catheter is inserted into an artery in the leg and then advanced through the aorta into the blocked regions of the coronary arteries. After positioning in the occluded region of the artery, the balloon is inflated with a pressurized saline solution which opens the artery restoring blood flow by pressing the atherosclerotic plaque into the vessel wall. Angioplasty is a widely performed procedure with the coronary arteries and is a much less expensive alternative to coronary bypass surgery. The best patients for angioplasty are those with single occlusions and this method is preferred over bypass grafting because of the significantly reduced expense. The reformation of plaque deposits in arteries (restenosis) following angioplasty, however, is a major clinical problem encountered in as high as 40 percent of patients. Because reduction of health care costs is a major national priority, development of effective new preventative methods for restenoses is an important national priority