Serum Cesium, Rhenium, and Rubidium in Rheumatoid Arthritis Patients.

A considerable attention has been focused on the possible association between ultra-trace elements (UTEs) status and pathogenesis of many diseases including rheumatoid arthritis (RA). UTEs have important roles in numerous metabolic processes. Serum Cs, Rb, and Re levels in RA are not studied previously. The correlation of serum Cs, Rb, and Re levels with the well-known serological parameters, anticyclic citrullinated protein antibody (ACPA), C-reactive protein (CRP), ESR, and rheumatoid factor (RF) is also not studied previously. The present study aimed to measure the level and the correlation between serum UTEs with various blood tests results in RA patients. Serum Cs, Rb, Re, ACPA, CRP, RF, and ESR were measured in Iraqi RA patients who have a positive ACPA (ACPA > 25 U/ml) and compared with healthy individuals. There were significant elevations (p < 0.05) in serum levels of all the measured parameters as compared with those of the healthy control group except Rb and uric acid which have not been changed. Subgrouping of patients according to the results of CRP and RF leads to different results. In the low-CRP group, the high-RF subgroup showed an elevation of ACPA, Cs, and ESR in comparison with the low-RF patients. In the high-CRP group, the patients with high RF showed an increase in the levels of Cs, Rb, ESR, and ACPA. The patient group with high RF and high CRP showed more significant correlations between serum UTEs and serological tests. Serum levels of UTEs were significantly altered in RA patients. The variations in the serum levels of the measured parameters in RA need more investigation to explore the possible association between these UTEs and RA. RA subgroups, according to the results of CRP and CPA, produce more and various information than taking RA as a whole group in the estimation of UTEs.

99mTc-labeled vasopressin peptide as a radiopharmaceutical for small-cell lung cancer (SCLC) diagnosis.

The 99mTc-labeled conjugates of the vasopressin (AVP) peptide and of its analogue d(CH2)5[D-Tyr(Et2)-Ile4-Eda9]AVP (AVP(an)) have been synthesized using the technetium complexes with tetradentate tripodal chelator (the tris(2-mercaptoethyl)amine (NS3)) and the monodentate isocyanide ligand (CN-peptide). The conjugates exhibit high stability in the presence of 100 times the molar excess of standard amino acids cysteine or histidine and also satisfactory stability in human serum. The 99mTc(NS3)(CN-AVP) and 99mTc(NS3)(CN-AVP(an)) ability of binding to small-cell lung cancer (SCLC) cell line H69 was studied in vitro. The results suggest that the novel vasopressin conjugate 99mTc(NS3)(CN-AVP(an)) is a desirable compound for imaging oncogene receptors overexpressed in SCLC cells and can be an important basis for further consideration the conjugate as a potential diagnostic radiopharmaceutical for patients suffering from small-cell lung cancer.

Bone marrow dosimetry using blood-based models for radiolabeled antibody therapy: a multiinstitutional comparison.

UNLABELLED: Standardization of marrow dosimetry is of considerable importance when estimating dose-response for a multicentered clinical trial involving radionuclide therapy. However, it is only within the past five years that the intercomparison of marrow dosimetry results among separate clinical trials that use the same agent has become scientifically feasible. In this work, we have analyzed reported marrow dosimetry results from radioimmunotherapy trials and recalculated marrow absorbed doses at a central facility using a standard blood model with patient-specific source data. The basic approach used in the American Association of Physicists in Medicine (AAPM)/Sgouros marrow dosimetry methodology was common to calculation performed at all participating institutions, including the central facility. Differences in dose estimates associated with starting assumptions and the exact implementation of the AAPM/Sgouros calculation methodology used by the source institutions and the central facility were quantified and compared. METHODS: Data from 22 patients enrolled in radiolabeled antibody clinical trials were randomly selected from 7 participating institutions for the assessment of marrow dose. The analysis was restricted to those patients who were treated with 131I- or 186Re-labeled antibody and had no marrow involvement. Calculation of bone marrow dose at each participating institution was unique to the trial or institution, but all used some form of the AAPM/Sgouros blood model approach. The central facility adopted a marrow dosimetry model based on the AAPM/Sgouros model for radiolabeled antibodies using the standard MIRD approach to the remainder-of-body contribution. A standardized approach to account for variations in patient mass was used for the remainder-of-body component. To simplify clinical implementation, regional marrow uptake and time-dependent changes in the marrow-to-blood concentration ratio were not included. Methods of formatting the collection of standard datasets useful in defining dose-response parameters are also presented. RESULTS: Bone marrow doses were calculated according to the method described for each of the 22 patients based on the patient-specific data supplied by the participating institutions. These values were then individually compared with the marrow doses originally reported by each institution. Comparison of the two calculation methods was expressed as a ratio of the marrow doses for each patient. The mean ratio for the dose estimates at the participating institution calculation compared with the central laboratory value was 0.920 +/- 0.259 (mean +/- SD), with a range from 0.708 to 1.202. CONCLUSION: The independent use of the AAPM/Sgouros method blood model approach to marrow dosimetry has brought these dose estimates to within 30% of the results obtained centrally compared with substantially higher uncertainties reported previously. Variations in calculation methodology or initial assumptions adopted by individual institutions may still contribute significant uncertainty to dose estimates, even when the same data are used as a starting point for the calculation comparison shown here. A clinically relevant, standard method for marrow dosimetry for radiolabeled antibodies is proposed as a benchmark for intercomparison purposes. A parameter sensitivity analysis and a summary discussion of the use of this model for potentially improving dose-response data correlation are also presented.

Biologic dosimetry of 188Re-HDD/lipiodol versus 131I-lipiodol therapy in patients with hepatocellular carcinoma.

UNLABELLED: One approach to treatment of primary hepatocellular carcinoma (HCC) is intraarterial injection of (131)I-lipiodol. Although clinical results have been positive, the therapy can be improved by using (188)Re instead of (131)I as the radionuclide. (188)Re is a high-energy beta-emitter, has a shorter half-life than (131)I, and has only low-intensity gamma-rays in its decay. The present study compared the cytotoxic effect of the radionuclide therapy in HCC patients treated with (131)I-lipiodol and (188)Re-4-hexadecyl 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD)/lipiodol. To this end, dicentric chromosomes (DCs) were scored in metaphase spreads of peripheral blood cultures. The equivalent total-body dose was deduced from the DC yields using an in vitro dose-response curve. METHODS: Twenty (131)I-lipiodol treatments and 11 (188)Re-HDD/lipiodol treatments were performed on, respectively, 16 and 7 patients with inoperable HCC. Patients received a mean activity of 1.89 GBq of (131)I-lipiodol or 3.56 GBq of (188)Re-HDD/lipiodol into the liver artery by catheterization. For each patient, a blood sample was taken during the week before therapy. A blood sample was also taken 7 and 14 d after administration for the patients treated with (131)I-lipiodol and 1 or 2 d after administration for the patients treated with (188)Re-HDD/lipiodol. RESULTS: The mean DC yield of (188)Re-HDD/lipiodol therapy (0.087 DCs per cell) was significantly lower than that of (131)I-lipiodol therapy (0.144 DCs per cell) for the administered activities. Corresponding equivalent total-body doses were 1.04 Gy for (188)Re-HDD/lipiodol and 1.46 Gy for (131)I-lipiodol. Data analysis showed that, in comparison with (131)I-lipidol, (188)Re-HDD/lipiodol yielded a smaller cytotoxic effect and a lower radiation exposure for an expected higher tumor-killing effect. CONCLUSION: (188)Re is a valuable alternative for (131)I in the treatment of HCC with radiolabeled lipiodol, and a dose escalation study for (188)Re-HDD/lipiodol therapy is warranted.

188Re-labeled anti-epidermal growth factor receptor humanized monoclonal antibody h-R3: labeling conditions, in vitro and in vivo stability.

The use of antibodies as targeting agents for the delivery of radioisotopes to tumors is an appealing concept that has received widespread attention since the advent of monoclonal antibody (mAb) technology. The present study describes the (188)Re-direct labeling of anti-epidermal growth factor receptor (EGF-R) humanized mAb h-R3; the analytical methods for quality control of radiopharmaceuticals such as instant thin layer chromatography-silica gel (ITLC-SG); the immunoreactivity and biological recognition of the target antigen assessment of the radiolabeled molecule using flow cytometry analysis; in vitro stability studies using saline 0.9% solution, cysteine, diethylenetriaminepentaacetic acid (DTPA), human serum and human serum albumin (HSA) 1% challenge; and the assessment of in vivo stability through biodistribution studies in normal Balb/c mice. No fragmentation of the reduced molecules was found using 2-ME as a reducing agent. Labeling efficiency was greater than 98.5 +/- 0.6% of rhenium-188 (188Re) bound to IgG1 after 5 h, as determined by paper chromatography in saline 0.9% solution. Radiocolloids determined by albumin impregnated ITLC was 1.04 +/- 0.07% in all cases. The biological activity measured by flow cytometry analysis showed an immunoreactivity fraction and the biological recognition of the target antigen overexpressed on H-125 human lung adenocarcinoma cell line greater than 87%. Challenge studies with cysteine, DTPA, human serum and HSA 1% demonstrated no evidence of transcomplexation of 188Re to DTPA or HSA and showed that 30% and 85% of the 188Re-radiolabeled was transcomplexed to human serum and to 100 mM cysteine after 24 h for human serum and 1 h incubation for cysteine at 37 masculine C, respectively. Biodistribution studies indicated no accumulation of the radiolabeled antibodies in normal organs.

186Re-liposome labeling using 186Re-SNS/S complexes: in vitro stability, imaging, and biodistribution in rats.

UNLABELLED: Liposomes are important carriers for controlling the spatial and temporal distribution of drug molecules or other bioactive molecules. Radiolabeled liposomes have potential applications in diagnostic imaging and radionuclide therapy. The purpose of this study was to develop a practical method for labeling liposomes with therapeutic rhenium radionuclides, using (186)Re as an example. METHODS: An SNS pattern ligand, N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA), and an S pattern ligand, benzene thiol (BT), were used to make 2 kinds of (186)Re-SNS/S complexes, (186)Re-BMEDA and (186)Re-BMEDA + BT. These (186)Re-SNS/S complexes were mixed with neutral liposomes encapsulating cysteine or (NH(4))(2)SO(4) to prepare (186)Re-liposomes. The in vitro labeling stability of (186)Re-liposomes was investigated by incubation in 50% fetal bovine serum/50% phosphate-buffered saline, pH 7.4, at 37 degrees C. Rat distribution studies of (186)Re-liposomes after intravenous injection were also performed. RESULTS: The labeling efficiencies of (186)Re-liposomes were 52.9%-81.3% depending on the (186)Re-SNS/S complex chosen and whether cysteine- or (NH(4))(2)SO(4)-encapsulated liposomes were used. (186)Re-(NH(4))(2)SO(4) liposomes labeled with (186)Re-BMEDA had the best in vitro labeling stability in serum with 89.8% +/- 3.1% of the radioactivity associated with liposomes at 24 h and 76.2% +/- 5.1% at 96 h. A specific activity of 1.85 GBq (50 mCi) of (186)Re per 50 mg of phospholipid could be achieved with good labeling stability. Biodistributions were followed for 72 h and showed good in vivo stability for (186)Re-liposomes that was characterized by a slow blood clearance and a gradually increasing spleen accumulation. (186)Re-BMEDA alone had fast blood clearance and no accumulation in spleen. CONCLUSION: A practical method for labeling liposomes with (186)Re using (186)Re-SNS/S complexes is described. The labeled (186)Re-liposomes were stable in serum and in vivo and could potentially be useful for radionuclide therapy.

[Antioxidant properties of rhenium cluster complexes with butyric acid derivatives in blood plasma and erythrocytes]. / Antyoksydantni vlastyvosti klasternykh kompleksiv reniiu z deiakymy pokhidnymy maslianoï kysloty u plazmi krovi ta erytrotsytakh.

The antioxidant action of rhenium cluster complexes with isobutiric and gamma-aminobutiric acids were studied in vitro. It was established that strong antiradical properties were found in the reaction with stable radical diphenylpycrylhydrazile Re2(i-C3H7COO)4Cl2, [Re2(GABA)2Cl5(H2O)]Cl.2H2O. The chemiluminescence investigation of antioxidant properties of both substances Re2(i-C3H7COO)4Cl2 and [Re2(GABA)2Cl5(H2O)]Cl.2H2O has established that these properties are realized in the blood plasma and erythrocytes, but to different extent.

Biodistribution of 131I-, 186Re-, 177Lu-, and 88Y-labeled hLL2 (Epratuzumab) in nude mice with CD22-positive lymphoma.

UNLABELLED: Radioimmunotherapy (RIT) is a new and effective treatment modality in patients with non-Hodgkin's lymphoma. The monoclonal antibody (mAb) hLL2 (epratuzumab), a humanized mAb directed against the CD22 antigen, and which internalizes, can be labeled with various radionuclides. The biodistribution of hLL2 labeled with (131)I, (186)Re, (177)Lu, and (88)Y was studied in nude mice with subcutaneous human lymphoma xenografts in order to determine the most suitable of these four radionuclides for RIT with hLL2. METHODS: Human Ramos lymphoma xenografts were transplanted in cyclophosphamide-pretreated athymic BALB/c mice. Four groups of mice were injected intravenously with (131)I-, (186)Re-, (88)Y-, or (177)Lu-labeled hLL2, respectively. To determine the nonspecific tumor uptake, two groups of mice received (88)Y-labeled or (131)I-labeled control antibody, cG250. The biodistribution of the radiolabel was determined 1, 3, and 7 days postinjection (p.i.). RESULTS: Radiolabeled hLL2 had a higher tumor uptake than the nonspecific mAb at all time-points, irrespective of the radiolabel used. Tumor accretion of (88)Y- and (177)Lu-hLL2 was higher than tumor uptake of (131)I- and (186)Re-hLL2. Activity in the bone, represented by the femur without bone marrow, was higher for (177)Lu- and (88)Y-hLL2 than for (131)I- and (186)Re-hLL2 on day 7 p.i. CONCLUSION: The use of the residualizing radiolabels (88)Y and (177)Lu in combination with a mAb directed against an internalizing antigen resulted in higher uptake and better retention of the radiolabel in the tumor.

Dosimetry of 188Re-hydroxyethylidene diphosphonate in human prostate cancer skeletal metastases.

UNLABELLED: 188Re-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. METHODS: Thirteen 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. RESULTS: The 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.

High-yield synthesis of the terminal 188Re triple bond N multiple bond from generator-produced [188ReO4](-).

A novel procedure for the high-yield preparation of Re-188 radiopharmaceuticals containing a terminal Re identical with N multiple bond is described. This method involves the reaction of [(188)Re][ReO(4)](-) with N-methyl S-methyl dithiocarbazate (DTCZ), as donor of nitrido nitrogen atoms, sodium oxalate and SnCl(2) to afford a mixture of two intermediate compounds. When this mixture is reacted with the sodium salt of a dithiocarbamate ligand (L) of the type Na[R(2)N-C(=S)S] (R = CH(3), CH(3)CH(2), CH(3)CH(2)CH(2)), the formation of the bis-substituted, neutral complexes [(188)Re][Re(N)(L)(2)] is easily obtained in high yield (> 95%). The complexes [(188)Re][Re(N)(L)(2)] were characterized by chromatographic methods, and by comparison with the corresponding complexes prepared at macroscopic level starting from a non-radioactive rhenium precursor. Biodistribution studies were carried out in rats. Results showed that the complexes [(188)Re][Re(N)(L)(2)] exhibited the same biological behavior of the analogous Tc-99m complexes reported previously. The easy application of the new synthetic procedure indicates that it could be conveniently employed for preparing a large class of new Re-188 complexes having potential utilization in nuclear medicine as therapeutic agents.

Investigations of directly labeling antibodies with rhenium-188.

Methods for labeling antibodies with 99mTc cannot be used without modification for radiorhenium despite the similar chemistries, in part because of a lower redox potential of rhenium and therefore a greater tendency to reoxidize. We have investigated conditions for directly labeling B72.3 IgG with 188Re via both mercaptoethanol and stannous ion antibody reduction. The reduced 188Re was stabilized for transchelation as the glucoheptonate complex and transchelated in the presence of excess stannous ion. End points were low "non-specific" binding (i.e. labeling in the absence of antibody reduction) and increased stability to cysteine challenge. By both methods, labeling efficiencies after about 15 minutes averaged 58.77% with as little as 4% non-specific binding. Specific activities of 15 muCi/microgram was achieved after 1.5 hours. By investigating labeling condition, it was possible to improve the stability of the label on stannous ion reduced antibody such that the in vitro and in vivo properties of 188Re were largely independent of labeling method. For example, losses of 188Re due to oxidation (16%) and to cysteine (7%) during 37 degrees C serum incubations for 24 hours were identical for both methods. Furthermore, after the administration to normal mice, whole body clearance and the accumulations of 188Re at 2.5 and 24 hours in blood and in most organs were also independent of labeling method. In conclusion, two different direct labeling methods provided a 188Re-labeled antibody with identical stabilities and with in vivo properties not greatly different from that seen for the same antibody radiolabeled directly with 99mTc.

[Bone-seeking behavior of rhenium and yttrium complexes]. / Zur Osteotropie von Rhenium- und Yttrium-Komplexen.

The results of experimental work on rats with strontium (85SrCl2, 89SrCl2) and yttrium (90Y) in a citrate complex demonstrate high affinity to bone. Rhenium perrhenat (186Re) Re-colloid and Re-methylene-diphosphonate were rapidly eliminated without bone affinity.