Furn F. Knapp

New radioiodinated methyl-branched fatty acids for cardiac studies

The effects of 3-methyl substitution on the heart retention and metabolism of 3-R,S-methyl-(BMIPP) and 3,3-dimethyl-(DMIPP) analogues of 15-(p-iodophenyl)-pentadecanoic acid (IPP) were studied in rats. Methyl substitution considerably increased the myocardial half-time values in fasted rats: IPP, 5–10 min; BMIPP, 30–45 min; DMIPP, 6–7 h. Because of the observed differences in the relative myocardial uptake and retention of these agents, an evaluation of the subcellular distribution profiles and the distribution of radioactivity within various lipid pools extracted from cell components was performed. Studies with DMIPP in food-deprived rats have shown high levels of the free fatty acid and only slow conversion to triglycerides. These data are in contrast to the rapid clearance of the straight chain IPP analogue and rapid incorporation into triglycerides, and suggest that the prolonged myocardial retention observed with DMIPP in vivo may result from inhibition of β oxidation. Subcellular distribution studies have shown predominant association of DMIPP and BMIPP with the mitochondrial and microsomal fractions, while IPP was primarily found in the cytoplasm. Because of the unique “trapping” properties and the high heart: blood ratios, [123I]DMIPP should be useful for evaluation of aberrations in regional myocardial uptake.

Repeated Bone-Targeted Therapy for Hormone-Refractory Prostate Carcinoma: Randomized Phase II Trial With the New, High-Energy Radiopharmaceutical Rhenium-188 Hydroxyethylidenediphosphonate

PURPOSE We investigated the effect of repeated bone-targeted therapy with rhenium-188 hydroxyethylidenediphosphonate (HEDP) in patients with progressive, hormone-resistant prostate carcinoma and bone pain. The aim of this study was to determine the pain palliation and the antitumor effect of rhenium-188 HEDP treatments. PATIENTS AND METHODS Sixty-four patients were randomly assigned to one of two groups for radionuclide therapy with rhenium-188 HEDP; patients of group A received a single injection, patients of group B received two injections (interval, 8 weeks). After therapy, patients were followed-up by assessment of pain palliation and clinical outcome until death. RESULTS In both groups, toxicity was low, with moderate thrombopenia and leukopenia (maximum common toxicity criteria grade of 2). The effectiveness of rhenium-188 HEDP for pain palliation was better in the repeated treatment group (group B), with a response rate and time of response of 92% and 5.66 months, respectively (P =.006 and P =.001). In group B, 11 (39%) of 28 patients had a prostate-specific antigen decrease of more than 50% for at least 8 weeks, compared with two (7%) of 30 patients in the single-injection group (group A). The median times to progression of group A and group B were 2.3 months (range, 0 to 12.2 months) and 7.0 months (range, 0 to 24.1 months), respectively (P =.0013), and the median overall survival times were 7.0 months (range, 1.3 to 36.7 months) and 12.7 months (range, 4.1 to 32.2 months), respectively (P =.043). CONCLUSION Compared with single-injection therapy, repeated bone-targeted therapy with rhenium-188 HEDP administered to patients with advanced progressive hormone-refractory prostate carcinoma enhanced pain palliation and improved progression-free and overall survival. Larger studies are justified to further evaluate the use of rhenium-188 HEDP.

Dose escalation study with rhenium-188 hydroxyethylidene diphosphonate in prostate cancer patients with osseous metastases.

Abstract.The aim of this study was to determine the maximum tolerated dose of rhenium-188 hydroxyethylidene diphosphonate (HEDP) in prostate cancer patients with osseous metastases who are suffering from bone pain. Twenty-two patients received a single injection of escalating doses of carrier-added 188Re-HEDP [1.3 GBq (35 mCi), 2.6 GBq (70 mCi), 3.3 GBq (90 mCi) and 4.4 GBq (120 mCi)]. Blood counts and biochemical parameters were measured weekly over a period of 8 weeks. Haematological toxicity (WHO grading) of grade 3 or 4 was considered unacceptable. Clinical follow-up studies including methods of pain documentation (medication, pain diary) were performed for 6 months after treatment. In the 1.3-GBq group, no haematological toxicity was observed. First haematotoxic results were noted in those patients with a dose of 2.6 GBq 188Re-HEDP. In the 3.3-GBq group, one patient showed a reversible thrombopenia of grade 1, one a reversible thrombopenia of grade 2 and three a reversible leukopenia of grade 1. In the 4.4-GBq group, thrombopenia of grades 3 and 4 was observed in one and two patients (baseline thrombocyte count <200×109/l), respectively, and leukopenia of grade 3 was documented in one patient. The overall nadir of thrombopenia was at week 4. The individual, maximum percentage decrease in thrombocytes in the 1.3-, 2.6-, 3.3- and 4.4-GBq groups was 17%, 40%, 60% and 86%, respectively. In two patients, a transient increase in serum creatinine was observed (max. 1.6 mg/dl). Pain palliation was reported by 64% of patients, with a mean duration of 7.5 weeks. The response rate seemed to increase with higher doses, reaching 75% in the 4.4-GBq group. It is concluded that in prostate cancer patients, the maximum tolerated dose of 188Re-HEDP is 3.3 GBq if the baseline thrombocyte count is below 200×109/l. In patients with thrombocyte counts significantly above 200×109/l, a dose of 4.4 GBq might be tolerable. Thrombo- and leukopenia are the most important side-effects. Pain palliation can be achieved in 60%–75% of patients receiving a dose of 2.6 GBq or more of 188Re-HEDP. Studies in a larger patient population are warranted to evaluate further the palliative effect of 188Re-HEDP.

The continuing important role of radionuclide generator systems for nuclear medicine

In this review, the continuing importance and status of development of radionuclide generator systems for nuclear medicine are discussed. Radioisotope costs and availability are two important factors, and both nuclear reactors and accelerator facilities are required for production of the parent radioisotopes. Radionuclide generator research is currently focused on the development of generators which provide radioisotopes for positron emission tomography (PET) applications and daughter radioisotopes for various therapeutic applications which decay primarily by particle emission. Generator research continues to be influenced by developments and requirements of complementary technologies, such as the increasing availability of PET. In addition, the availability of a wide spectrum of tumor-specific antibodies, fragments, and peptides for radio-immunodiagnosis and radioimmunotherapy has stimulated the need for generator-derived radioisotopes. The advantages of treatment of arthritis of the synovial joints with radioactive particles (radiation synovectomy) may be expected to be of increasing importance as the elderly population increases, and many of these agents are prepared using generator-derived radioisotopes such as yttrium-90 and rhenium-188. Therapeutic use of the “in vivo generator” is a new approach, where the less radio-toxic parent radioisotope is used to prepare tissue-speciic therapeutic agents. Following in vivo site localization, decay of the parent provides the daughter for therapy at the target site. The principal foundation of most diagnostic agents will continue to require technetium-99m from the molybdenum-99/technetium-99m (“Moly”) generator. With the limited availability of nuclear reactors and facilities necessary for production and processing of fission 99mTc and the significant issues and problems associated with radioactive waste processing, however, the possibility of utilizing lower specific activity 99Mo produced from neutron activation of enriched 98Mo may become practical in the future.

Iodine-123-labelled fatty acids for myocardial single-photon emission tomography: current status and future perspectives

Renewed interest in the clinical use of iodine-123-labelled fatty acids is currently primarily focused on the use of iodine-123-labelled 15-(p-iodophenyl)pentadecanoic acid (IPPA) and “modified” fatty acid analogues such as 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) which show delayed myocardial clearance, thus permitting single-photon emission tomographic imaging. Interest in the use of BMIPP and similar agents results from the differences which have often been observed in various types of heart disease between regional myocardial uptake patterns of [123I]BMIPP and flow tracer distribution. Although the physiological basis is not completely understood, differences between regional fatty acid and flow tracer distribution may reflect alterations in important parameters of metabolism which can be useful for patient management or therapy planning. These tracers may also represent unique metabolic probes for correlation of energy substrate metabolism with regional myocardial viability. The two agents currently most widely used clinically are123I-labelled IPPA and BMIPP. While [123I]IPPA is commercially available as a radiopharmaceutical in Europe (Cygne) and Canada (Nordion), multicenter trials are in progress in the United States as a prelude to approval for broad use. [123I]BMIPP was recently introduced as Cardiodine for commercial distribution in Japan (Nihon Medi-Physics, Inc.). [123I]BMIPP is also being used in clinical studies on an institutional approval basis at several institutions in Europe and the United States. In this review, the development of a variety of radioiodinated fatty acids is discussed. The results of clinical trials with [123I]IPPA and [123I]BMIPP are discussed in detail, as are the future prospects for fatty acid imaging.

Processing of reactor-produced 188W for fabrication of clinical scale alumina-based 188W/188Re generators

Abstract The traditional technique for processing of reactor-irradiated 186 W-enriched tungsten oxide (WO 3 ) targets involves formation of 188 W-sodium tungstate solutions by target dissolution in 0.1 M NaOH. Following long irradiations (> 21 days) in the ORNL High Flux Isotope Reactor (HFIR) the 186 WO 3 targets contain a NaOH-insoluble 188 W-labeled black solid (approx. 30–50% of total activity) which decreases the yield and specific activity of the processed 188 W (e.g. 5–6 mCi/mg 186 W for a 79-day irradiation). The black material is postulated to represent a “tungsten blue” insoluble polymeric form of tungsten oxide, which we have now found to dissolve in 0.1 M NaOH containing 5% sodium hypochlorite solution. Complete dissolution results in a significant increase in the yield and specific activity of sodium 188 W-tungstate. As an alternative approach, irradiated 186 W-enriched metal targets dissolve in sodium hydroxide solution by cautious addition of 188 W-tungstate solutions prepared from processing of such metal targets show no evidence of residual black insoluble material. Specific activity values for completely dissolved HFIR-irradiated 186 W targets have increased to 10 mCi/mg (43.5 days) and 12.9 mCi/mg (49.2 days). Large clinical scale (> 1 Ci) generators prepared from hypochlorite-processed 186 W oxide or peroxide-processed 186 W metal targets exhibit the expected 188 Re high yield and low 188 W breakthrough.

Evaluation of the metabolism in rat hearts of two new radioiodinated 3-methyl-branched fatty acid myocardial imaging agents.

The biological fate of two new radioiodinated 3-methyl-branched fatty acids has been evaluated in rat hearts following intravenous administration. Methylbranching was introduced in [15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) and 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP) to inhibit β-oxidation. The goals of these studies were to correlate the effects of methyl-branching on the incorporation of these agents into the various fatty acid pools and subcellular distribution profiles, and to relate these data to the myocardial retention properties. The properties of BMIPP and DMIPP were compared with the 15-(p-iodophenyl)pentadecanoic acid straight-chain analogue (IPP). Differences in the heart retention of the analogues after intravenous administration in rats correlated with differences observed in subcellular distribution patterns. The dimethyl DMIPP analogue showed the longest retention and the highest association with the mitochondrial and microsomal fractions (34%, 38%) 30 min after injection. These data are in contrast to the rapid clearance of the straight-chain IPP analogue which showed much lower relative association with the mitochondria and microsomes (18%, 15%). The distribution patterns of each analogue in the various lipid pools appeared consistent with the expected capacity of the analogues to be metabolized by β-oxidation. In contrast to the rapid oxidation of the straight-chain IPP analogue, the 3-monomethyl BMIPP analogue appeared to undergo slower oxidation and clearance, whereas the dimethyl-branched DMIPP analogue was apparently not catabolized by the myocardium. All three analogues showed some incorporation into triglycerides. The metabolism patterns of the branched analogues reported here may provide useful information in the description of the mechanisms by which BMIPP and DMIPP are retained in rat myocardium.

Rhenium-188 hydroxyethylidene diphosphonate: a new generator-produced radiotherapeutic drug of potential value for the treatment of bone metastases

The search for an ideal radioisotope for systemic radiotherapy continues. As a generator-produced radioisotope emitting both beta and gamma rays and having a short physical half-life of 16.9 h, rhenium-188 is a very good potential candidate for systemic radiotherapy. In this study, we labeled hydroxyethylidene diphosphonate (HEDP) with188Re and analyzed the biodistribution and bone uptake following intravenous injection in rats to assess its potential for clinical use. The rats were injected with approximately 14.8 MBq (0.4 mCi)188Re-HEDP in a volume of 0.1 ml intravenously and then sacrificed at 1 h, 24 h, or 48 h (four rats at each time). Samples (about 0.1 g) of lung, liver, kidney, spleen, testis, muscle, stool, and bone (thoracic vertebra) were taken and weighed carefully. In addition, a 1-ml sample of blood was drawn from the heart and 1 ml of urine was taken from the urinary bladder immediately after killing. Tissue concentrations were calculated and expressed as percent injected dose per gram or per milliliter (% ID/g or ml). Bone lesions were created in the right tibial bone in three rabbits to calculate the lesion to normal uptake ratio (UN ratio). The biodistribution data showed that the radioactivity in the bone tissue was as high as 1.877% ID/g at 1 h and that it climbed to 2.017% ID/g at 4 h. The activity level in the kidney was highest at 1 h but declined rapidly throughout the study. The radioactivities in the lung, liver, muscle, spleen, testis, blood, and stool were all lower than 0.3% ID/g at I h and also declined rapidly. The biological half-life in bone was the longest (60.86 h). In contrast, the biological half-lives in muscle and blood were short (2.99 h and 6.21 h respectively). The concentrations of radioactivity in muscle, spleen, testis, and stool were quite low throughout the study. Most of the radiotracer was excreted by the urinary system. The L/N ratio was 4.23±0.21 in rabbits injected with188Re-HEDP and 4.25±0.23 in those injected with technetium-99m methylene diphosphonate. In conclusion, we would suggest that188Re-HEDP is a very good potential candidate for the treatment of bone metastases because of the following characteristics: (1) it is generator produced; (2) it has a short half-life; (3) it emits gamma rays suitable for imaging; (4) there is highly selective uptake in the skeletal system and bone lesions; and (5) it has a low non-target uptake and rapid clearance in nonosseous tissue.

Sustained Availability of 99mTc: Possible Paths Forward

The availability of 99mTc for single-photon imaging in diagnostic nuclear medicine is crucial, and current availability is based on the 99Mo/99mTc generator fabricated from fission-based molybdenum (F 99Mo) produced using high enriched uranium (HEU) targets. Because of risks related to nuclear material proliferation, the use of HEU targets is being phased out and alternative strategies for production of both 99Mo and 99mTc are being evaluated intensely. There are evidently no plans for replacement of the limited number of reactors that have primarily provided most of the 99Mo. The uninterrupted, dependable availability of 99mTc is a crucial issue. For these reasons, new options being pursued include both reactor- and accelerator-based strategies to sustain the continued availability of 99mTc without the use of HEU. In this paper, the scientific and economic issues for transitioning from HEU to non-HEU are also discussed. In addition, the comparative advantages, disadvantages, technical challenges, present status, future prospects, security concerns, economic viability, and regulatory obstacles are reviewed. The international actions in progress toward evolving possible alternative strategies to produce 99Mo or 99mTc are analyzed as well. The breadth of technologies and new strategies under development to provide 99Mo and 99mTc reflects both the broad interest in and the importance of the pivotal role of 99mTc in diagnostic nuclear medicine.

Studies on the preparation and isomeric composition of 186Re- and 188Re-pentavalent rhenium dimercaptosuccinic acid complex.

The preparative conditions for 186Re(V)DMSA and 188Re(V)DMSA (DMSA = meso-dimercaptosuccinic acid), β-emitting radiopharmaceuticals that have been shown to localize in medullary thyroid carcinoma, require modification depending on the amount of carrier rhenium and the chemical form and medium in which the rhenium is supplied. Preparative conditions are described for use with carrier-free 188ReO4- in saline, and for use with 186ReO4- in saline, sodium hydroxide or nitric acid. Preparation of 186Re(V)DMSA (carrier present up to 2 mg per 2.5 ml reaction volume) requires a DMSA:SnCl2:Re ratio of 10:5:1 at 100 °C for 30 min. Addition of excess nitric acid or hydrochloric acid up to a concentration of 155 HIM does not reduce the yield from 100%. A commercial DMSA kit vial (e.g. Amerscan DMSA) can be used for preparation of 188Re(V)DMSA (carrier free) provided the required activity is in a volume of less than 1 ml per vial. A convenient method of concentrating the 188Re generator eluate to the required volume is described.