Measurement of 24-hr whole-body retention of 99mTc-MDP with a thyroid uptake probe (author's transl)

A new method for measurement of 24-hr whole-body retention (WBR) of 99mTc-MDP, using a thyroid uptake probe was established and its clinical significance was evaluated in various bone diseases. (1) Reproducibility of 24-hr WBR in 9 patients was very good. Correlation coefficient was 0.997 and coefficient of variability was only 1.83%. (2) Radiochemical purity of 99mTc-MDP was 97.8 +/- 0.7% (n = 5), indicating no significant inter-lot variations. (3) 24-hr WBR of normal adult males (n = 5) was 30.0 +/- 4.9%, which was significantly elevated compared to the reported 99mTc-HEDP WBR of 19.2 +/- 1.7%. Whole-body retentions of chronic renal failure, metastatic bone disease and hyperthyroidism groups were significantly elevated compared to that of the normal group. However, WBR of steroid-induced osteoporotic group was significantly decreased. Based on these results, this thyroid uptake probe method was simple, reproducible and accurate to measure 24-hr WBR of 99mTc-MDP. Quantification of WBR of 99mTc-MDP was of great clinical value to diagnose metabolic bone disease and to follow-up metabolic and metastatic bone diseases.     

Evaluation by using radionuclide uptake of bone in Paget's disease of bone: special reference to treatment with calcitonin

Bone scintigraphy using 99mTc-MDP was performed on 2 patients with Paget's disease of bone before and after the treatment with a synthetic eel calcitonin analogue [Asu1,7)-eel calcitonin, ECT] at a dose of 40 U per day. All pagetic lesions showed markedly the increased accumulation of the radionuclide. The uptake ratio, defined as the count rate of 99mTc-MDP over each bone lesion to that over the control bone, was calculated. The response to the calcitonin therapy was evaluated with the uptake ratio of the radionuclide. The uptake ratio decreased markedly within the first 3 months of the treatment, in association with a palliation of bone pain, while the serum alkaline phosphatase activities which had been within the normal range or slightly high before the treatment did not show any significant change or did not reflect a clinical feature (e.g. bone pain) with the treatment. Thus, the uptake ratio on the bone scintigram seemed to offer the most sensitive and most reliable information for the evaluation of calcitonin treatment of Paget's disease of bone.     

Quantitative study of diffuse increased 99mTc-methylene diphosphonate accumulation of both kidneys

Patients with diffuse increased accumulation in both kidneys on 99mTc-MDP bone scintigram were evaluated quantitatively. Among 1,100 cases, 7 (0.63%) showed this finding. The accumulation density ratios of kidneys/lumbal vertebra in A/D exchanged images of these patients were compared with control group, so that these ratios of patient group were higher than control group statistically. In conclusion, the accumulation density ratio was made the index of diffuse increase accumulation in both kidneys on 99mTc-MDP bone scintigram.     

Reduced Bone Mineral Density and Bone Metabolism in Aquaporin-1 Knockout Mice

An overt phenotype of aquaporin-1 knockout(AQP1 ko) mice is growth retardation, suggesting possible defects in bone development and metabolism. In the present study, we analyzed the bone mineral density(BMD), bone calcium and phosphorus contents, and bone metabolism in an AQP1 ko mouse model. The BMD of femurs in AQP1 ko mice was significantly lower than that of litter-matched wildtype mice as measured by dual energy X-ray absorptiometry. Consistently, the contents of bone total calcium and phosphorus were also significantly lower in AQP1 ko mice. The reduced BMD caused by AQP1 deficiency mainly affect male mice. Bone metabolic activity, as indicated by 99mTc-MDP absorption measurements, was remarkably reduced in AQP1 ko mice. These results provide the first evidence that AQP1 play an important role in bone structure and metabolism.     

99mTc(CO)3-labeled pamidronate and alendronate for bone imaging

Bone scintigraphy with (99m)Technetium-methylenediphosphonate ((99m)Tc-MDP) or (99m)Technetium-hydroxymethylenediphosphonate ((99m)Tc-HMDP) presents several limitations, namely low specificity, uncertainty in the radiopharmaceutical's molecular structure and long acquisition time after injection. Aiming to find bone-seeking radiotracers based on the core fac-[(99m)Tc(CO)(3)](+) with improved chemical and biological properties, we synthesized new conjugates (pz-PAM and pz-ALN), comprising a pyrazolyl-diamine chelating unit (pz: N,N,N donor atom set) for metal stabilization and a pendant pamidronate (PAM) or alendronate (ALN) moiety for bone targeting. The reaction of the conjugates with fac-[(99m)Tc(CO)(3)](+) yielded (> 95%) the stable complexes fac-[(99m)Tc(CO)(3)(pz-PAM)](-) (2a) and fac-[(99m)Tc(CO)(3)(pz-ALN)](-) (3a), which have been characterized by comparing their HPLC gamma-traces with the UV-vis traces of the Re surrogates 2 and 3, respectively. 2a and 3a bind strongly onto hydroxyapatite. The biodistribution studies in Balb-c mice have shown that 2a and 3a presented an high bone uptake (2a 18.3 ± 0.6% I.D./g, 3a 17.3 ± 6.1% I.D./g, at 1 h post injection), similar to (99m)Tc-MDP (17.1 ± 2.4% I.D./g, at 1 h post injection), with comparable clearance from most tissues and increased total excretion (2a 66% I.D., 3a 67% I.D. and (99m)Tc-MDP 49% I.D., at 1 h post injection). The bone-to-blood (2a 86.2, 3a 74.7) and the bone-to-muscle ratios (2a 77.7, 3a 79.0) are higher than the ones found for (99m)Tc-MDP (70.9, 47.9), at 4 h post injection. Planar whole-body gamma camera images of the rats injected with the (99m)Tc(CO)(3)-labeled pamidronate (2a) and alendronate (3a) confirmed the overall adequate biological profile of the new radiotracers for bone imaging.     

Double tracer autoradiography of bone tumor using 3H-thymidine and radionuclides for diagnostic purpose

Whole body distribution and accumulation of radionuclide for diagnostic purpose such as 99mTc-MDP (methylene diphosphonate), 67Ga-citrate (67Ga) and 201Tl-chloride (201Tl) in implanted osteosarcoma of human origin were evaluated by macroautoradiography of Balb/c nude mouse. 3H-thymidine of which uptake has a close relation to growth pattern of tumors was used for a partner of target nuclide in double tracer technique to examine the distribution characteristics. Separated distribution pattern of coupled nuclides was imaged by a difference both of half life and energy of radiation between radionuclides. The distribution pattern of each target nuclide and 3H-thymidine were compared to clarify distribution characteristics respectively in specimen. 67Ga and 201Tl were taken around the tumor and the mode of their distribution was identical to that of 3H-thymidine. Uptake of 67Ga in tumor was much higher. 99mTc-MDP accumulated in the central zone of the tumor and its pattern was quite different from that of 3H-thymidine. From above result it was demonstrated that the accumulation mechanism of 67Ga, 201Tl and 99mTc-MDP are quite different in the tumor each other. So we concluded that our method of double tracer technique was useful for evaluation of distribution pattern of radionuclides for diagnostic purpose.     

Progress in Targeted Alpha-Particle-Emitting Radiopharmaceuticals as Treatments for Prostate Cancer Patients with Bone Metastases

Bone metastasis remains a major cause of death in cancer patients, and current therapies for bone metastatic disease are mainly palliative. Bone metastases arise after cancer cells have colonized the bone and co-opted the normal bone remodeling process. In addition to bone-targeted therapies (e.g., bisphosphonate and denosumab), hormone therapy, chemotherapy, external beam radiation therapy, and surgical intervention, attempts have been made to use systemic radiotherapy as a means of delivering cytocidal radiation to every bone metastatic lesion. Initially, several bone-seeking beta-minus-particle-emitting radiopharmaceuticals were incorporated into the treatment for bone metastases, but they failed to extend the overall survival in patients. However, recent clinical trials indicate that radium-223 dichloride (²²³RaCl₂), an alpha-particle-emitting radiopharmaceutical, improves the overall survival of prostate cancer patients with bone metastases. This success has renewed interest in targeted alpha-particle therapy development for visceral and bone metastasis. This review will discuss (i) the biology of bone metastasis, especially focusing on the vicious cycle of bone metastasis, (ii) how bone remodeling has been exploited to administer systemic radiotherapies, and (iii) targeted radiotherapy development and progress in the development of targeted alpha-particle therapy for the treatment of prostate cancer bone metastasis.     

Synthesis of novel nano-radiotracer for in-vivo bone imaging: 99mTc- citric acid based PEG dendrimer and its conjugation with alendronate

Bone scan is the test that guide physician to diagnose diseases in the bone at the early stage, to prevent metastases to other organs. In this study, citric acid dendrimer conjugation with alendronate was synthesized. Obtained product was confirmed by FT-IR and TEM. Cytotoxicity assay at different concentrations showed no toxicity on normal cell line compared to control group. Radiolabeling process was optimized by Box-Behnken software which is a computational method to determine optimum of important radiolabeling parameters. Optimized parameter for reducing agent, dendrimer-G₂-alendronate, and time for shaking was 1 mg, 12.3 mg, and 25 min respectively. For determination of in-vivo accumulation of ^99mTc-dendrimer-G₂-alendronate, SPECT imaging was done. Images showed high accumulation of radio-tracer in the skeletal compared to ^99mTc-MDP which is the frequent bone scan agent. All in all, obtained results confirmed our hypothesis that the dendrimer-G₂-alendronate can be noteworthy nano-radiopharmaceuticals to bone cancer imaging at early stage.     

Scintigraphic imaging of autotransplanted splenic grafts by 99mTc-labeled heat-damaged erythrocytes

Splenectomy is known to increase the risk of bacterial infection. Recently splenic autotransplantation has been suggested as a method of preserving splenic function. In order to demonstrate the viability of transplanted tissue, spleen scintigraphy using 99mTc labeled heat damaged erythrocytes were carried out. So far 21 studies have done in 12 patients. Spleen scans were positive 1 month after surgery, though images showed poor contrast against considerable background of bone marrow and blood pool. The quality of the images much improved five to twelve months after surgery. Functioning splenic autografts could be also shown by scintigraphy using 99mTc sulfur colloid, but the image quality was poorer, particularly within the early stage after operation. Labeling yields were 79.8% on the average, ranging from 45.6-92.3%, that affected little the quality of images. Important techniques in the splenic autotransplantation imaging include a thorough elimination of free 99mTcO4- before injection and to use comparatively small volume of damaged erythrocytes.     

Synthesis and evaluation of a series of 99mTc-labelled zoledronic acid derivatives as potential bone seeking agents

Developing novel superior bone-seeking radiopharmaceuticals for the detection of malignant bone lesions could further improve the diagnostic value of routine bone scanning. A series of radiolabeled diphosphonates (^99mTc-EIPrDP, ^99mTc-EIBDP and ^99mTc-EIPeDP) have been designed and synthesized successfully in high chemical yields and radiochemical purity. The in vitro and in vivo biological properties were systematically investigated and compared. The biodistribution in mice shows that ^99mTc-EIPrDP has higher bone uptake (13.3 ± 1.23) than those of ^99mTc-EIBDP and ^99mTc-EIPeDP (11.7 ± 0.28 and 8.69 ± 0.04 %ID/g) at 1–2 h post injection. It also has the highest uptake ratio of bone to muscle, spleen and heart, respectively, and faster blood clearance in early times. The present study indicates that ^99mTc-EIPrDP holds great promise as a bone imaging agent.     

Ether and crown ether-containing cationic 99mTc complexes useful as radiopharmaceuticals for heart imaging

While radiopharmaceutical research has been focused on the development of target-specific radiotracers for early detection and radiotherapy of cancers in the last decade, there is a limited effort on new cationic 99mTc radiotracers for heart imaging. This review will summarize some of the most recent developments in ether- and crown ether-containing cationic 99mTc radiotracers that have a fast liver clearance with a heart/liver ratio substantially better than that of 99mTc-Sestamibi and 99mTc-Tetrofosmin, the two commercial 99mTc radiopharmaceuticals currently available for myocardial perfusion imaging. Fast liver clearance might shorten the duration of imaging protocols (<30 min post-injection), and allow for early acquisition of heart images of high quality. Improvement of heart/liver ratio may permit better detection of the presence and extent of coronary artery disease. Identification of such a new radiotracer that allows for the improved non-invasive delineation of myocardial perfusion would be of considerable benefit in treatment of patients with suspected coronary artery disease.     

Resveratrol in management of bone and spinal cancers

Bone cancer is a malignant primary tumour of the bone with different typing, such as, osteosarcoma, chondrosarcoma, Ewing’s sarcoma and fibrosarcoma. Despite the clinical efficacy of conventional therapies of bone cancer, most patients eventually relapse and the disease remains incurable. Therefore, new therapeutic strategies are needed to improve patient outcome. In this review article, we have discussed the role of resveratrol in preventing bone and spinal cancers and therapeutics. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a natural polyphenol, which has been widely reported as an anticancer molecule. Resveratrol exhibits multiple tumour-suppressing activities in bone cancer by affecting a series of critical events. It has the protective effects against oxidative injury, possesses antiproliferative activity and induces apoptosis in cancer cells. Resveratrol might be a good option for the treatment of different types of bone and spinal cancers.     

In vitro incorporation studies of 99mTc–alendronate sodium at different bone cell lines

Bisphosphonates can be labeled with Technetium-99m (^99mTc) and are used for bone imaging because of their good localization in the skeleton and rapid clearance from soft tissues. Over the last decades bone scintigraphy has been used extensively in the evaluation of oncological patients to provide information about the sites of bone lesions, their prognosis and the effectiveness of therapy by showing the sequential changes in tracer uptake. Since the lesion visualization and lesion/bone ratio are important utilities for a bone scanning radiopharmaceutic; in this study incorporation of ^99mTc labeled alendronate sodium (^99mTc–ALD) was evaluated in U₂OS (human bone osteosarcoma) and NCI-H209 (human bone carcinoma) cell lines. ALD was directly labeled by ^99mTc, radiochemical purity and stability of the complex were analyzed by radioactive thin layer chromatography and radioactive high performance liquid chromatography studies. For cell incorporation study, NCI-H209 and U₂OS cell lines were used with standard cell culture methods. The six well plates were used for all experiments and the integrity of each cell monolayer was checked by measuring its transepithelial electrical resistance (TEER) with an epithelial voltammeter. Results confirmed that ALD was successfully radiolabeled with ^99mTc. ^99mTc–ALD incorporated with NCI-H209 and U₂OS cells. The uptake percentages of ^99mTc–ALD in NCI-H209 and U₂OS cell lines were found significantly different. Since ^99mTc–ALD highly uptake in cancer cell line, the results demonstrated that radiolabeled ALD may be a promising agent for bone cancer diagnosis.     

代谢组学法分析骨髓抑制模型小鼠血清小分子代谢产物

骨髓抑制是恶性肿瘤患者化疗后常见的症状,研究骨髓抑制造成体内代谢产物的变化可以为诊断骨髓抑制病症发展状况及采用药物治疗提供思路。采用雄性BalB/C小鼠腹腔注射环磷酰胺建立骨髓抑制模型,通过气相色谱-质谱(GC-MS)对正常与造模小鼠血液代谢产物进行指纹图谱分析,然后采用主成分分析(PCA)和正交偏最小方差判别分析(OPLS-DA)对代谢组学数据进行多维统计分析。与对照组相比,骨髓抑制模型小鼠血浆中潜在的差异表达代谢标志物有15个,其中葡萄糖-1-磷酸、对硝基苯酚、乙酰苯胺、可的松、烟酰胺、马钱苷、咖啡酸、亚油酸和油酸这9种物质的表达差异有统计学意义(P0.05)。结果表明,代谢产物可作为骨髓抑制研究中的重要标记物,有助于揭示化疗所致骨髓抑制的发病机制,判断疾病发展阶段以及后续治疗手段的有效性。     

Prospective study to assess the clinical efficacy of bone scintigraphy--ROC analysis

The value of preoperative bone scans in patients with primaly breast and prostate cancer was evaluated prospectively. The methodology and some clinical results were described previously. The clinical efficacy of the bone scan was assessed by using ROC analysis and we obtained the following results. 1) Preoperative bone scan of carcinomas of the breast is effective for patients with clinical stage IIIA, IIIB and IV. It is not so effective for patients with clinical stage I and II, but there is no denying the importance of it, because it provides a base-line scan for comparison to subsequent scans obtained in the postoperative period. 2) Preoperative bone scan of prostate carcinomas is effective, especially for clavicle, the ribs and the cervical spine, when compared with bone X-ray. 3) Bone scan is effective means for patients who were diagnosed uncertainly to have bone metastasis.     

Synthesis and biological evaluation of a novel <Superscript>99m</Superscript>Tc complex of HYNIC-conjugated aminomethylenediphosphonate as a potential bone imaging agent

A conjugate of 6-hydrazinopyridine-3-carboxylic acid (HYNIC) with aminomethylenediphosphonic acid (AMDP) was synthesized through a multiple-step reaction. HYNIC–AMDP could be labeled easily and efficiently with ^99mTc using N-(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)glycine (tricine) as coligand to form the ^99mTc–HYNIC–AMDP complex in high yield (> 95%). Its partition coefficient indicated that it was a good hydrophilic complex. The biodistribution studies of ^99mTc–HYNIC–AMDP in normal ICR mice showed that this complex had high bone uptake and low or negligible accumulation in non-target organs. As compared with ^99mTc–MDP, ^99mTc–HYNIC–AMDP had a higher bone uptake and the ratios of bone/blood and bone/muscle at early time after injection, suggesting that it could be potentially useful for bone imaging at an earlier time after injection according to further investigations of the biological behavior of this complex.     

99mTc水杨醛Schiff碱配合物的制备与生物分布

One novel complex of ^99mTc-salicylidene-tyrosine Schiff base was designed and synthesized, and its biodistribution was investigated. The theoretical simulation revealed that the cis- and trans-isomers might co-exist in aqueous solution. A yield higher than 90% under the optimal condition of synthesis was obtained. Good water-solubility was demonstrated. Very little uptakes in muscle, brain, heart and S-180 sarcoma, as well as very rapid blood clearance were revealed in mice. Good accumulation in bone was shown. At 1h postinjection the bone uptake was 10.9% ID/g. At 3 and 5h postinjection, bone-to-muscle ratios were 19.0 and 9.3, and bone-to-blood ratios were 31.6 and 28. 9, respectively. The result indicates a bone imaging potency of the complex.     

Bone marrow scintigraphy with 111In-chloride--a clinical value for the hematological diseases

Bone marrow scintigraphy with indium chloride (111In) was performed in fifty-one patients with the hematological diseases. The results of the investigation were that 1. in all patients, as well as in patients with aplastic anemia, no correlation was there between the degree of the indium chloride accumulation and peripheral blood counts, 2. in patients with aplastic anemia and pure red cell aplasia (PRCA) a tendency to reduction in uptake of indium chloride in bone marrow, 3. in patients with these two good correlation between the degree of indium chloride accumulation and histology of the erythroid bone marrow, but in patients with chronic myelocytic leukemia (CML) and atypical leukemia no correlation between the two, so it seemed unlikely that indium chloride should reflect the effective production of erythrocytes, 4. four patients with leukemia were studied with indium chloride bone marrow imaging two times to evaluate their responses to chemotherapy, and peripheral expansion was no change or reduced in two patients with acute myelocytic leukemia (AML) and one patient with acute lymphocytic leukemia (ALL) who obtained complete remission, but on the other hand, it enlarged in one patient with acute myelocytic leukemia who obtained partial remission, and 5. in two patients with chronic myelocytic leukemia it enlarged up to the ankle joints, which was considerably specific.     

Application of macroautoradiography and instantimage in radiopharmaceutical research

The evaluation of the pharmacokinetics of pure, beta radiopharmaceuticals is not possible with scintigraphy. Both whole-body autoradiography (WBAR) and Packard Instantimager, a device for rapid imaging, were used to study the whole body distribution of γ- and β-emitting radionuclides (^99mTc-MDP,^99mTc-sulfur colloid, or¹⁸⁸Re-HEDP), and results obtained from both methods were compared. The biodistribution of^99mTc-MDP and¹⁸⁸Re-HEDP were seen mainly in bones including skull, spine, and vertebrae of spine and cardiac and skeletal muscles. The^99mTc-sulfur colloid localized in liver, bone marrow, and spleen. The resolution of WBAR is superior than that of Packard Instantimager. However, the advantage of Packard Instantimager is that rapid imaging within few minutes is possible with it, while WBAR imaging requires several hours to days.     

Myocardial reversibility detection. Rest NTG99mTc-MIBI versus201TI reinjection. Preliminary results

This study test whether sublingual administration of nitroglycerin (NTG) could improve the capability of^99mTc-MIBI to detect reversibility in exercise-induced perfusion defects and to compare it with the²⁰¹TI stress-redistribution-reinjection protocol. Twenty-one patients with previous myocardial infarction were submitted to exercise, rest and NTG rest^99mTc-MIBI imaging (3-day protocol). The patients also underwent exercise, redistribution and reinjection²⁰¹Tl myocardial scintigraphy. A total of 273 myocardial segments were analyzed: 76 (28%) had irreversible defects on stress-rest^99mTc-MIBI, 60 (79%) appeared as fixed defects and 16 (21%) were reversible on NTG rest^99mTc-MIBI. Of the 78 myocardial segments with irreversible defects on standard stress-redistribution thallium cardiac imaging, 63 (81%) did not change and 15 (19%) demonstrated enhanced uptake of thallium after reinjection. Data show that rest NTG^99mTc-MIBI study improves the detection of reversible myocardium versus standard exercise/rest^99mTc-MIBI and achieve similar results than²⁰¹Tl reinjection protocol.