Bone pain arising from secondary skeletal malignancy constitutes one of the most common types of chronic pain among patients with cancer which can lead to rapid deterioration of the quality of life. Radionuclide therapy using bone-seeking radiopharmaceuticals based on the concept of localization of the agent at bone metastases sites to deliver focal cytotoxic levels of radiation emerged as an effective treatment modality for the palliation of symptomatic bone metastases. Bone-seeking radiopharmaceuticals not only provide palliative benefit but also improve clinical outcomes in terms of overall and progression-free survival. There is a steadily expanding list of therapeutic radionuclides which are used or can potentially be used in either ionic form or in combination with carrier molecules for the management of bone metastases. This article offers a narrative review of the armamentarium of bone-targeting radiopharmaceuticals based on currently approved investigational and potentially useful radionuclides and examines their efficacy for the treatment of painful skeletal metastases. In addition, the article also highlights the processes, opportunities, and challenges involved in the development of bone-seeking radiopharmaceuticals. Radium-223 is the first agent in this class to show an overall survival advantage in Castration-Resistant Prostate Cancer (CRPC) patients with bone metastases. This review summarizes recent advances, current clinical practice using radiopharmaceuticals for bone pain palliation, and the expected future prospects in this field.

Peptide receptor radionuclide therapy (PRRT) is a site-directed targeted therapeutic strategy that specifically uses radiolabeled peptides as biological targeting vectors designed to deliver cytotoxic levels of radiation dose to cancer cells, which overexpress specific receptors. Interest in PRRT has steadily grown because of the advantages of targeting cellular receptors in vivo with high sensitivity as well as specificity and treatment at the molecular level. Recent advances in molecular biology have not only stimulated advances in PRRT in a sustainable manner but have also pushed the field significantly forward to several unexplored possibilities. Recent decades have witnessed unprecedented endeavors for developing radiolabeled receptor-binding somatostatin analogs for the treatment of neuroendocrine tumors, which have played an important role in the evolution of PRRT and paved the way for the development of other receptor-targeting peptides. Several peptides targeting a variety of receptors have been identified, demonstrating their potential to catalyze breakthroughs in PRRT. In this review, the authors discuss several of these peptides and their analogs with regard to their applications and potential in radionuclide therapy. The advancement in the availability of combinatorial peptide libraries for peptide designing and screening provides the capability of regulating immunogenicity and chemical manipulability. Moreover, the availability of a wide range of bifunctional chelating agents opens up the scope of convenient radiolabeling. For these reasons, it would be possible to envision a future where the scope of PRRT can be tailored for patient-specific application. While PRRT lies at the interface between many disciplines, this technology is inextricably linked to the availability of the therapeutic radionuclides of required quality and activity levels and hence their production is also reviewed.

Lutetium-177 ((177)Lu) is a late entrant into the nuclear medicine therapy arena but is expected to become one of the most widely used therapeutic radionuclides. This paper analyses the reason for the increasing preference of (177)Lu as a therapeutic radionuclide. While the radionuclidic properties favor its use for several therapeutic applications, the potential for large scale production of (177)Lu is also an important aspect for its acceptability as a therapeutic radionuclide. This introductory discussion also summarizes some developing clinical uses and suggested future directions for applications of (177)Lu.

This article presents a concise review of the production of no-carrier-added (NCA) Lu-177 by the 'indirect' route by irradiating ytterbium-176 (Yb-176)-enriched targets. The success of this production method depends on the ability to separate the microscopic amounts of NCA Lu-177 from bulk irradiated ytterbium targets. The presence of Yb+3 from the target in the final processed Lu-177 will adversely affect the quality of Lu-177 by decreasing the specific activity and competing with Lu+3 complexation since ytterbium will follow the same coordination chemistry. Ytterbium and lutetium are adjacent members of the lanthanide family with very similar chemical properties which makes the separation of one from the other a challenging task. This review provides a summary of the methods developed for the separation and purification of NCA Lu-177 from neutron irradiated Yb-176-enriched targets, a critical assessment of recent developments and a discussion of the current status of this Lu-177 production method.

Background: This review provides a comprehensive summary of the production of 177Lu to meet expected future research and clinical demands. Availability of options represents the cornerstone for sustainable growth for the routine production of adequate activity levels of 177Lu having the required quality for preparation of a variety of 177Lu-labeled radiopharmaceuticals. The tremendous prospects associated with production of 177Lu for use in targeted radionuclide therapy (TRT) dictate that a holistic consideration should evaluate all governing factors that determine its success. Methods: While both “direct” and “indirect” reactor production routes offer the possibility for sustainable 177Lu availability, there are several issues and challenges that must be considered to realize the full potential of these production strategies. Results: This article presents a mini review on the latest developments, current status, key challenges and possibilities for the near future. Conclusion: A broad understanding and discussion of the issues associated with 177Lu production and processing approaches would not only ensure sustained growth and future expansion for the availability and use of 177Lu-labeled radiopharmaceuticals, but also help future developments.

Targeted therapy with radiopharmaceuticals labeled with beta-emitting radionuclides is a rapidly growing nuclear medicine clinical specialty exemplified by the great progress attained over the last decade in the use of radiolabeled peptides for treatment of receptor expressing tumors, most notably for therapy of somatostatin-expressing solid tumors. Only a relatively limited number of beta-emitting radioisotopes are readily available for such applications, and reactor-produced lutetium-177 (Lu) has emerged as a key player in this field, because of its attractive radionuclidic properties (T1/2 6.7 days; Emax β 0.498 MeV; γprin 208 keV, 11%). In addition, relatively high specific activity (SA) Lu is available via both “direct” (>25 Ci/mg) irradiation of enriched Lu or “indirect” production from Yb (> 90 Ci/mg). Clinical applications of Lu have focused not only on strategies for targeting tumors, but also for therapeutic treatment of chronic disease such as arthritis (synovectomy) and for treatment of metastatic bone pain (palliation). In this special issue, the articles will cover the production of Lu, preparation of a variety of radiopharmaceutical agents and the principle clinical applications of this important therapeutic radionuclide.

This paper discusses the benefits of obtaining 99mTc from non–fission reactor–produced low-specific-activity 99Mo. This scenario is based on establishing a diversified chain of facilities for the distribution of 99mTc separated from reactor-produced 99Mo by (n,γ) activation of natural or enriched Mo. Such facilities have expected lower investments than required for the proposed chain of cyclotrons for the production of 99mTc. Facilities can receive and process reactor-irradiated Mo targets then used for extraction of 99mTc over a period of 2 wk, with 3 extractions on the same day. Estimates suggest that a center receiving 1.85 TBq (50 Ci) of 99Mo once every 4 d can provide 1.48–3.33 TBq (40–90 Ci) of 99mTc daily. This model can use research reactors operating in the United States to supply current 99Mo needs by applying natural natMo targets. 99Mo production capacity can be enhanced by using 98Mo-enriched targets. The proposed model reduces the loss of 99Mo by decay and avoids proliferation as well as waste management issues associated with fission-produced 99Mo.

This article presents a concise review of the production of no-carrier-added (NCA) 177Lu by the 'indirect' route by irradiating ytterbium-176 (176Yb)-enriched targets. The success of this production method depends on the ability to separate the microscopic amounts of NCA 177Lu from bulk irradiated ytterbium targets. The presence of Yb+3 from the target in the final processed 177Lu will adversely affect the quality of 177Lu by decreasing the specific activity and competing with Lu+3 complexation since ytterbium will follow the same coordination chemistry. Ytterbium and lutetium are adjacent members of the lanthanide family with very similar chemical properties which makes the separation of one from the other a challenging task. This review provides a summary of the methods developed for the separation and purification of NCA 177Lu from neutron irradiated 176Yb-enriched targets, a critical assessment of recent developments and a discussion of the current status of this 177Lu production method.

This work describes the installation, use, and quality control (QC) of the alumina-based tungsten-188 (W-188)/rhenium-188 (Re-188) generators provided by the Oak Ridge National Laboratory (ORNL). In addition, methods used for concentration of the Re-188-perrhenate bolus and preparation of Re-188-labeled HDD (4-hexadecyl-2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol) for trans-arterial administration for therapy of nonresectable liver cancer also are described. The W-188/Re-188 generator has a long useful shelf-life of several months and is a convenient on-site Re-188 production system. Re-188 has excellent therapeutic and imaging properties (T-1/2 16.9 hours; E-beta max 2.12 MeV; 155-keV gamma ray, 15%) and is cost effectively obtained on demand by saline elution of the generator. The clinical efficacy of a variety of Re-188-labeled agents has been demonstrated for. several therapeutic applications. Because of the favorable physical properties of Re-188, several Re-188-labeled agents are being developed and evaluated for the treatment of non resectable/refractory liver cancer. Re-180-labeled HDD has been the most widely studied of these agents for this application and has been introduced into clinical trials at a number of institutions. The trans-arterial administration of Re-188-labeled agents for treatment of inoperable liver cancer requires use of high-level (1-2 Ci) W-188/Re-188 generators. The handling of such high levels of Re-188 imposes radiological precautions normally not encountered in a radiopharmacy and adequate care and ALARA (ie, "As Low As Reasonably Achievable") principles must be followed. The ORNL generator provides consistently high Re-188 yields (>75%) and low W-188 parent breakthrough (<10(-3)%) over an extended shelf-life of several months. However, the high elution volumes (20-40 mL for 1-2 Ci generators) can require concentration of the Re-188 bolus by postelution passage through silver cation chloride trapping columns used in the cost-effective tandem cation/anion column system. The silver column removes the high levels of chloride anion as insoluble AgCl, thus allowing subsequent specific trapping of the perrhenate anion on the small (QMA SeaPak) anion column. This method permits subsequent elution of Re-188-perrhenate with a small volume of saline, providing a very high activity-concentration solution. Because the Re-188-specific volume-activity concentration continually decreases with time, the tandem system is especially effective method for extending the useful generator shelf-life. Low elution flow rates (<1 mL/min) minimize any high back pressure which may be encountered during generator/tandern column elution when using tightly packed, small-particle-size commercial columns. In-house preparation of silver cation columns is recommended since the chloride trapping capacity is essentially unlimited, it is inexpensive and not limited in availability to any one supplier, and back pressure can be eliminated by the use of larger particles. Methods for the preparation of Re-188-HDD have been optimized and this agent can be obtained in high yield (80%).

The 2006 EANM Congress, held in Athens, Greece, was once again a major event in the nuclear medicine scientific and educational calendar. The scientific programme, which included the second biennial ISRTRD meeting, confirmed the major developments taking place in (1) the diagnostic and prognostic uses of nuclear medicine imaging (both in PET and in single-photon studies), (2) radionuclide therapies, (3) radiochemistry and radiopharmacy, and (4) physics. This paper outlines the major findings in each of these areas.

BACKGROUND:In cases of in-stent restenosis, intracoronary radiotherapy with beta-emitters and gamma-emitters has been shown to reduce the risk of repeat restenosis. The present randomised, placebo-controlled study addresses the question of whether intracoronary radiotherapy applied by the easy-to-handle Rhenium liquid-filled angioplasty balloon system is also able to reduce the angiographic re-restenosis rate in stents. METHODS AND RESULTS:At our center, from May 2000 to December 2003, 165 patients (mean age 64+/-10, median 65 years; 127 men, 38 women) with symptomatic in-stent restenosis underwent either intracoronary brachytherapy or sham procedure. Index clinical and angiographic parameters were largely comparable in both groups. Radiation therapy was performed with a standard percutaneous transluminal coronary angioplasty (PTCA) balloon catheter inflated with liquid Rhenium in the redilated in-stent restenosis for 240-890, mean 384+/-125 s with low pressure (3 atm) in order to reach 30 Gy at 0.5 mm depth of the vessel wall. In 82 patients, intracoronary radiotherapy was carried out without complications, but one of the 83 patients who underwent sham procedure suffered small myocardial infarction. During follow-up, stent thrombosis with subsequent non-Q-wave myocardial infarction occurred in one patient in each group (6 days and 8 months after the procedure, respectively). At 6 months after the index procedure, repeat angiography was performed in 156 of the 164 patients with successful procedure (rate 95%): restenosis (stenosis >50% in diameter) or reocclusion was observed in only 19 of 78 (=24%) patients of the radiation but in 31 of 78 (=40%) patients of the sham procedure group (P=0.04). Event-free survival (free of death, myocardial infarction, target vessel revascularization) at 1 year was 87% for patients being radiated and 74% for patients having undergone sham procedure (P=0.05). CONCLUSIONS:Intracoronary radiation therapy with the liquid-filled beta-emitting Rhenium balloon is not only easy to perform, safe, and comparably inexpensive but also an effective option to prevent repeat restenosis and the need for target vessel revascularization in cases of in-stent restenosis.

The High Flux Isotope Reactor at the Oak Ridge National Laboratory provides the highest steady-state thermal neutron flux in the western world for a wide range of experiments and for isotope production. The highest available fluxes are located in a flux trap region created inside the nested fuel elements. The experimentally determined thermal and the empirically obtained epithermal flux values along the vertical axis of the peripheral target position were fit to cosine curves, with the thermal flux ranging from 1.1 x 10(15)ns(-1)cm(-2) at outer positions to 1.5 x 10(15)ns(-1)cm(-2) at the center. The corresponding epithermal flux ranged from 3.5 x 10(13) to 7.5 x 10(13)ns(-1)cm(-2), respectively. The fast neutron flux (En > or = 0.32 MeV in two positions and En > or = 1.5 MeV in two other positions) was approximately 6 x 10(14)ns(-1)cm(-2), corresponding to a fast to thermal ratio of approximately 0.4.

UNLABELLED188Re-Hydroxyethylidene diphosphonate ((188)Re-HEDP) was used in previous studies for the palliative treatment of metastatic bone pain. However, the kinetic and radiation-absorbed doses have not been well documented. Therefore, the aim of this study was to gather dosimetric data for (188)Re-HEDP.METHODSThirteen prostate cancer patients with skeletal involvement were treated with 2,700-3,459 MBq (mean dose, 3,120 MBq) (188)Re-HEDP. Patients underwent whole-body scans 3, 20, and 28 h after therapy. The effective half-life, residence time, and radiation-absorbed dose values were calculated for the whole body, bone marrow, kidneys, and bladder as well as for 29 bone metastases. The urinary excretion rate was determined in 6 urine samples of each patient collected over 48 h at 8-h intervals beginning immediately after the administration of (188)Re-HEDP. After injection of (188)Re-HEDP, blood samples were taken weekly for 6 wk, and platelet and leukocyte counts were performed.RESULTSThe mean effective half-life was 15.9 +/- 3.5 h in bone metastases, 10.9 +/- 2.1 h in the bone marrow, 11.6 +/- 2.1 h in the whole body, 12.7 +/- 2.2 h in the kidneys, and 7.7 +/- 3.4 h in the bladder. The following radiation-absorbed doses were calculated: 3.83 +/- 2.01 mGy/MBq for bone metastases, 0.61 +/- 0.21 mGy/MBq for the bone marrow, 0.07 +/- 0.02 mGy/MBq for the whole body, 0.71 +/- 0.22 mGy/MBq for the kidneys, and 0.99 +/- 0.18 mGy/MBq for the bladder. (188)Re-HEDP showed a rapid urinary excretion within the first 8 h after therapy, with 41% of the (188)Re-HEDP administered being excreted. Forty-eight hours after therapy, the excretion rate was 60% +/- 12%. Only 1 patient showed a decrease of platelet count below 100 x 10(9) counts/L. None of the patients presented with a decrease of leukocyte count below 3.0 x 10(9) counts/L.CONCLUSION(188)Re-HEDP is an effective radiopharmaceutical used in the palliative treatment of metastatic bone pain. The radiation-absorbed dose is acceptable for bone pain palliation with low doses for the normal bone marrow and the whole body.

Dietary triacylglycerols are a major source of energy for animals. The absorption of dietary triacylglycerols involves their hydrolysis to free fatty acids and monoacylglycerols in the intestinal lumen, the uptake of these products into enterocytes, the resynthesis of triacylgylcerols, and the incorporation of newly synthesized triacylglycerols into nascent chylomicrons for secretion. In enterocytes, the final step in triacylglycerol synthesis is believed to be catalyzed primarily through the actions of acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. In this study, we analyzed intestinal triacylglycerol absorption and chylomicron synthesis and secretion in DGAT1-deficient (Dgat1(-/-)) mice. Surprisingly, DGAT1 was not essential for quantitative dietary triacylglycerol absorption, even in mice fed a high fat diet, or for the synthesis of chylomicrons. However, Dgat1(-/-) mice had reduced postabsorptive chylomicronemia (1 h after a high fat challenge) and accumulated neutral-lipid droplets in the cytoplasm of enterocytes when chronically fed a high fat diet. These results suggest a reduced rate of triacylglycerol absorption in Dgat1(-/-) mice. Analysis of intestine from Dgat1(-/-) mice revealed activity for two other enzymes, DGAT2 and diacylglycerol transacylase, that catalyze triacylglycerol synthesis and apparently help to compensate for the absence of DGAT1. Our findings indicate that multiple mechanisms for triacylglycerol synthesis in the intestine facilitate triacylglycerol absorption.

1-Methylpiperidin-4-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (IPIP, Fig. 1) was investigated as a potential radioiodinated molecular probe targeted to the muscarinic receptor complex. The IPIP stereoisomers were synthesized via a chiral intermediate in >95% enantiomeric excess. The R-isomers demonstrated a M(1) to M(2) subtype selectivity of approximately 3 to 1 and the S-isomers demonstrated non-subtype selective binding in vitro. IPIP was radiolabeled with iodide-125 with an average radiochemical yield of 74.4% (+/-14.8, n = 5), specific activities >800 mCi/micromol, and radiochemical purities >97%. In vivo the Z-isomers demonstrated high uniform cerebral uptake suggesting non-subtype selective binding. In contrast, E-R-IPIP, after allowing a low uptake in M(2) rich areas to clear, demonstrated a retention of activity in M(1) and M(4) rich cerebral regions. In addition, the cerebral uptake of E-R-IPIP and Z-S-IPIP were inhibited by 70-90% via pretreatment with R-QNB, an established muscarinic antagonist. An ex vivo metabolism study demonstrated Z-S-IPIP was stable at the receptor site with an absence of radiolabeled metabolites.