Usefulness of competitive inhibitors of protein binding for improving the pharmacokinetics of <Superscript>186</Superscript>Re-MAG3-conjugated bisphosphonate (<Superscript>186</Superscript>Re-MAG3-HBP), an agent for treatment of painful bone metastases

Purpose  We have developed a ¹⁸⁶Re-mercaptoacetylglycylglycylglycine complex-conjugated bisphosphonate (¹⁸⁶Re-MAG3-HBP) for the treatment of painful bone metastases. We assumed competitive inhibitors of protein binding to be useful for procuring a favorable biodistribution of ¹⁸⁶Re-MAG3-HBP for the palliation of bone pain because it has been reported that the concurrent administration of ^99mTc-MAG3 and drugs with high affinity for serum protein produced competitive displacement at specific binding sites and enhanced total clearance and tissue distribution. Methods  The displacement effects of several protein-binding inhibitors on the protein binding of ¹⁸⁶Re-MAG3-HBP were investigated. Biodistribution experiments were performed by intravenously administering ¹⁸⁶Re-MAG3-HBP into rats with ceftriaxone as a competitive protein-binding inhibitor or saline. Results  The protein binding of ¹⁸⁶Re-MAG3-HBP in rat serum, human serum, and a human serum albumin solution was significantly decreased by the addition of ceftriaxone, which has high affinity for binding site I on serum albumin. In the biodistribution experiments, pretreatment with ceftriaxone enhanced the clearance of the radioactivity of ¹⁸⁶Re-MAG3-HBP in blood and nontarget tissues but had no effect on accumulation in bone. Conclusions  The findings suggested that the use of protein-binding competitive inhibitors would be effective in improving the pharmacokinetics of radiopharmaceuticals with high affinity for serum protein.     

Evaluation of toxicity and efficacy of 186Re-hydroxyethylidene diphosphonate in patients with painful bone metastases of prostate or breast cancer.

Twenty-eight patients (12 men with prostate cancer, 16 women with breast cancer) were included in a phase II trial to evaluate the efficacy of 186Re-hydroxyethylidene diphosphonate (HEDP) on pain from bone metastasis and the toxicity of this agent. METHODS: After intravenous administration of 1295 MBq 186Re-HEDP, the efficacy was evaluated by means of a daily log. RESULTS: We observed an objective response in 67% of prostate cancer patients and in 36% of breast cancer patients. The mean duration of response was 45 d for prostate cancer patients and 24 d for breast cancer patients. No major adverse effects were observed. Marrow toxicity did not exceed grade 2 for white blood cells and grade 3 for platelets using National Cancer Institute criteria. CONCLUSION: 186Re-HEDP provides safe symptomatic relief of pain in prostate cancer patients. The benefit of this treatment is less clear in breast cancer patients. Further studies should be conducted to evaluate treatment by 186Re-HEDP at an earlier stage of the disease.     

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

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.     

Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer

Rhenium-186 hydroxyethylidene diphosphonate (¹⁸⁶Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A phase 1 dose escalation study was performed using ¹⁸⁶Re-HEDP Twenty-four patients with hormone-resistant prostate cancer entered the study. Each patient had at least four bone metastases and adequate haematological function. Groups of at least three consecutive patients were treated with doses starting at 1295 MBq and increasing to 3515 MBq (escalated in increments of 555 MBq). Thrombocytopenia proved to be the dose-limiting toxicity, while leucopenia played a minor role. Early death occurred in one patient (10 days after administration) without clear relationship to the ¹⁸⁶Re-HEDP therapy. Transient neurological dysfunction was seen in two cases. Two patients who received 3515 MBq ¹⁸⁶Re-HEDP showed grade 3 toxicity (thrombocytes 25–50 × 10⁹/1), defined as unacceptable toxicity. After treatment alkaline phosphatase levels showed a transient decrease in all patients (mean: 26% ± 10% IUA; range: 11%–44%). Prostate-specific antigen values showed a decline in eight patients, preceded by a temporary increase in three patients. From this study we conclude that the maximally tolerated dose of ¹⁸⁶Re-HEDP is 2960 MBq. A placebo-controlled comparative study on the efficacy of ¹⁸⁶Re-HEDP has been initiated.     

Short- and long-term effects of 186Re-1,1-hydroxyethylidene diphosphonate in the treatment of painful bone metastases.

This study evaluates the short- and long-term therapeutic efficacy of 186Re-1,1-hydroxyethylidene diphosphonate (HEDP) in the palliation of painful bone metastases and the influence of variables before therapy in determining the characteristics of pain palliation. METHODS: Sixty patients with painful bone metastases from different tumor types were treated with 1406 MBq 186Re-HEDP. After treatment, the patients were followed up clinically at weekly intervals for the first month and monthly thereafter up to 1 y, until death or pain relapse. Pain response was graded as complete, partial, minimal, or absent using the Wisconsin test scoring system. Duration of pain relief, performance status, tumor markers, serum alkaline phosphatase levels, hematologic toxicity, and metastatic bone progression were also evaluated. RESULTS: Overall, 80% of individuals experienced prompt relief of pain, with 31% complete, 34% partial, and 15% minimal responses. Transient World Health Organization grade 1-2 hematologic toxicity was apparent, with a decrease in the mean platelet (32%) and mean leukocyte (18%) counts at 3 and 4 wk, respectively. The degree of pain response did not correlate with any pretreatment variable. The duration of pain relief ranged from 3 wk to 12 mo and correlated positively with the degree of response (P = 0.02) and negatively with pretreatment scintigraphic scores and alkaline phosphatase levels (P = 0.02). CONCLUSION: 186Re-HEDP is effective for fast palliation of painful bone metastases from various tumors. The effect tends to last longer if patients are treated early in the course of their disease.     

Preparation, stability studies and pharmacological behavior of [186Re]Re-HEDP.

99mTc-HEDP is widely used as a bone imaging agent and its Re analog [186Re]Re-HEDP is now well established as a therapeutic radiopharmaceutical for palliation of pain due to bone metastases. In the present paper, we report the work carried out for the preparation of stable 186Re-HEDP which retains RC purity up to 5 days when stored at 4 degrees C. 186Re was prepared by irradiation of natural Re metal at a flux of 3 x 10(13) neutrons/cm2/s for seven days and processed after a cooling period of four days. The specific activity of 186Re formed was approximately 35 mCi/mg. A complex with RC purity > 98% could be prepared by varying the reaction conditions. By carefully optimizing the reaction and storage conditions, a complex which was stable for over 4 days could be synthesized. Bio-distribution studies carried out in rats revealed approximately 30% bone uptake of 186Re-HEDP at 3 h postinjection which remained almost constant for 48 h, at which time there was negligible activity in other organs.     

186Re-HEDP in the treatment of patients with inoperable osteosarcoma.

The aim of this study was to examine the safety and efficacy of (186)Re-hydroxyethylidene diphosphonate (HEDP) as an adjuvant to external-beam radiotherapy (EBRT) in the treatment of patients with osteosarcoma. METHODS: Thirteen patients (9 male, 4 female; age range, 12-42 y) were treated with combination chemotherapy (standard U.K. protocol) and (186)Re-HEDP therapy (18.5 MBq/kg, intravenously), followed by EBRT. A full blood count; liver function test; and measurements of urea and electrolytes, glomerular filtration rate, and left ventricular function were performed on all patients before and after therapy. Tumor volume and composition were obtained from CT or MRI data. Dosimetric calculations were performed using the MIRD formalism. RESULTS: Of the 13 patients, 1 is still under follow-up. The median survival time was 36 mo (range, 12-216 mo) from diagnosis and 5 mo (range, 1-60 mo) from the last (186)Re-HEDP treatment. The mean tumor dose delivered with (186)Re-HEDP was calculated to be 5.8 Gy (range, 0.5-16 Gy). CT and MRI revealed the tumors to have a complex structure, comprising "ossified," "partially calcified," and "soft-tissue" components. Posttherapy scans showed a heterogeneous distribution of (186)Re-HEDP in the tumor mass: Although the "soft-tissue" component showed minimal uptake of the therapeutic dose, the "ossified component" showed intense uptake. The 3 long-term survivors in whom tumor sterilization was achieved received calculated mean tumor doses in the range of 2.0-3.1 Gy, which was believed to be an underestimate of the actual tumor doses delivered. CONCLUSION: This study indicates that a simple approach to tumor dosimetry based on mean tumor dose is inappropriate because it may underestimate the dose delivered to these heterogeneous tumors. The data also indicate that EBRT combined with a standard dose of 18.5 MBq/kg of (186)Re-HEDP does not provide a sufficient dose to achieve tumor sterilization. A dose estimation technique is required that is based on the determination of tumor dose at the individual voxel level and that is able to represent the heterogeneous uptake observed in these complex tumor structures with highly nonuniform composition. This, coupled with individualized dose escalation, may then achieve the goal of tumor sterilization.     

A comparative study of 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr in the treatment of painful skeletal metastases

AIM: The surface bone-seeking radiopharmaceuticals 188Re-HEDP, 186Re-HEDP and 153Sm-EDTMP, and the volume seeker 89Sr were investigated to determine the efficacy and toxicity in pain palliation of bone metastases. METHOD: The effect of treatment with 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr on pain symptoms, quality of life, and bone marrow function were studied. In total, 79 patients (18 with breast cancer and 61 with prostate cancer) were treated (31 patients with 188Re-HEDP, 15 patients each with 186Re-HEDP and 153Sm-EDTMP, and 18 patients with 89Sr). All patients were interviewed using standardized sets of questions before and after therapy weekly for 12 weeks. Blood counts were taken weekly for 6 weeks and after 12 weeks. RESULTS: In total, 73% of patients reported pain relief (77% after 188Re-HEDP, 67% after 186Re-HEDP 73% after 153Sm-EDTMP, and 72% after 89Sr). Fifteen percent of patients could discontinue their analgesics and were pain-free. Pain showed a decrease from 3.6+/-1.7 to a maximum of 2.2+/-1.8 at visual analogue scale in 10 steps (P<0.01). Patients described an improvement on the Karnofsky performance scale from 70+/-10% to 78+/-14% 12 weeks after treatment (P=0.15). There were eight patients with a thrombocytopenia grade I, two patients with grade II and one with grade III. The maximum nadir of platelet and leukocyte counts were observed between the 2nd to 5th week after treatment and was reversible within 12 weeks. There were no significant differences in pain palliation, Karnofsky performance status (KPS) and bone marrow toxicity between the different radionuclides (P=0.087-0.449). CONCLUSION: All radiopharmaceuticals were effective in pain palliation, without induction of severe side effects or significant differences in therapeutic efficacy or toxicity.     

188 Re-HEDP对体外成骨细胞增殖及细胞周期的影响

目的 观察不同剂量188Re-羟基亚乙基二膦酸盐(HEDP)近距离作用对成骨细胞增殖和细胞周期的影响.方法 在体外培养的成骨细胞中加入不同放射性浓度(0,1.85,9.61,48.00,240.50,462.50,832.50和1110.00 kBq/ml)188 Re-HEDP,继续培养24 h后检测细胞的放射性计数,了解成骨细胞摄取188Re-HEDP的能力.用四甲基偶氮唑蓝(MTT)法检测成骨细胞增殖能力.测定细胞碱性磷酸酶(ALP)活性,以明确成骨细胞分化功能.采用流式细胞仪检测细胞周期变化.结果 成骨细胞摄取188Re-HEDP的能力较强,188Re-HEDP≤1110.00 kBq/ml时未观察到结合平台期.受188.Re-HEDP刺激后成骨细胞生长增殖旺盛、分化加强,成骨细胞存活率为(113.67±3.22)%-(122.00±6.58)%,ALP值为(0.42±0.02)～(0.50±0.05)U/L;188Re-HEDP≥33.30 MBq/ml时成骨细胞凋亡率增加[(6.26±0.09)%]并随剂量增大.188Re-HEDP作用后处于合成期的成骨细胞百分率明显增加,为(22.32±2.31)%-(35.58±5.18)%.结论 188Re-HEDP可能刺激成骨细胞增殖和分化,使合成期的细胞百分率增高.188Re-HEDP超过33.30 MBq/ml时引起成骨细胞凋亡,且凋亡率与其放射性浓度呈正相关.     

Bone uptake studies in rabbits before and after high-dose treatment with 153Sm-EDTMP or 186Re-HEDP.

The aim of this animal study was to measure the bone uptake of (99m)Tc-hydroxymethylene diphosphonate (HDP) before and after high-dose treatment with (153)Sm-ethylenediaminetetramethylenephosphonate (EDTMP) or (186)Re-(tin)1,1-hydroxyethylidene diphosphonate (HEDP) to prove or disprove post-therapeutic alterations of bone uptake of radiolabeled bisphosphonates. METHODS: Quantitative bone scanning using 100 MBq (99m)Tc-HDP was performed on 12 rabbits before and 8 wk after radionuclide therapy with 1,000 MBq of either (153)Sm-EDTMP or (186)Re-HEDP. Whole-body images were acquired at 3 min, 3 h, and 24 h after injection, and the activities for the whole body, urinary bladder, and soft tissue were measured by region-of-interest technique. From these data, bone uptake was calculated as initial whole-body activity minus urinary excretion and remainder soft-tissue activity. RESULTS: In animals treated with (153)Sm-EDTMP (n = 6), no differences could be proven for the bone uptake of (99m)Tc-HDP at 24 h after injection before and after therapy (51.1% +/- 5.5% vs. 48.0% +/- 6.1%, P > 0.05). There were also no significant differences for the remainder soft-tissue activities and the urinary excretion rates before and after therapy. Similar results were obtained in rabbits treated with (186)Re-HEDP: Bone uptake (44.8% +/- 6.7% vs. 40.4% +/- 4.9%, P > 0.05) and urinary excretion revealed no significant differences before and after treatment. CONCLUSION: No significant impairment of bone uptake of (99m)Tc-HDP could be observed 8 wk after high-dose radionuclide bone therapy. Because both the biokinetic data obtained for (186)Re-HEDP and (153)Sm-EDTMP and the myelotoxic effects were quite similar in rabbits to those in patients, it seems justifiable to expect the same result (i.e., no significant alteration of bone uptake of radiolabeled bisphosphonates) in patients undergoing a second radionuclide therapy within 2-3 mo after standard treatment with (186)Re-HEDP or (153)Sm-EDTMP.     

Assessment of 186Re chelate-conjugated bisphosphonate for the development of new radiopharmaceuticals for bones

INTRODUCTION: The preferable pharmacokinetics of rhenium-186 (186Re)-monoaminemonoamidedithiol-conjugated or 186Re-mercaptoacetyltriglycine-conjugated bisphosphonates (BPs) suggested that the molecular design would be applicable to other radionuclides such as 68Ga, 99mTc, 153Sm and 177Lu. In this study, a key factor affecting the pharmacokinetics of a chelate-conjugated BP was investigated to estimate the validity and the applicability of molecular design. METHODS: Chemically inert and well-characterized tricarbonyl[186Re][(cyclopentadienylcarbonyl amino)-acetic acid]rhenium ([186Re]CpTR-Gly) was conjugated with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate and purified by high-performance liquid chromatography (HPLC) to prepare [186Re](1-{3-[tricarbonyl(cyclopentadienylcarbonyl amino)-acetylamido]-1-hydroxy-1-phosphono-propyl}-phosphonic acid)rhenium ([186Re]CpTR-Gly-APD). Plasma stability, plasma protein binding, hydroxyapatite (HA) binding and the pharmacokinetics of [186Re]CpTR-Gly-APD were compared with those of 186Re 1-hydroxyethylidene-1,1-diphosphonate (HEDP). The effect of HEDP coadministration and preadministration on the pharmacokinetics of [186Re]CpTR-Gly-APD was also determined. RESULTS: The HPLC-purified [186Re]CpTR-Gly-APD showed higher plasma stability, higher HA binding, higher bone accumulation and lower plasma protein binding than did 186Re-HEDP. However, HA binding of [186Re]CpTR-Gly-APD decreased to levels slightly higher than that of 186Re-HEDP at similar HEDP concentrations. Bone accumulation of [186Re]CpTR-Gly-APD also decreased to levels similar to that of 186Re-HEDP when [186Re]CpTR-Gly-APD was coinjected with HEDP equivalent to that in 186Re-HEDP. In contrast, HEDP pretreatment did not impair bone accumulation of the two 186Re-labeled compounds. However, a delay in blood clearance and an increase in renal radioactivity levels were observed particularly with 186Re-HEDP. CONCLUSIONS: Although 186Re-HEDP possessed HA binding and bone accumulation similar to those of [186Re]CpTR-Gly-APD, the specific activity of 186Re-labeled BPs was found to play a crucial role in bone accumulation and blood clearance. Thus, the molecular design of chelate-conjugated BP would be useful for the development of bone-seeking radiopharmaceuticals with a variety of radionuclides by selecting chelating molecules that provide high specific activities.     

Skeletal uptake and soft-tissue retention of 186Re-HEDP and 153Sm-EDTMP in patients with metastatic bone disease.

The aim of this study was to introduce a new quantification method for 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) and 186Re-(tin)1,1-hydroxyethylidene diphosphonate (HEDP) to separately measure bone uptake and soft-tissue retention of these radiopharmaceuticals. METHODS: Studies were performed on 23 men and 6 women undergoing radionuclide therapy for palliation of bone pain. Whole-body images were acquired at 3 min, 3-4 h, and 24-72 h after injection of 1,295 MBq 186Re-HEDP and 37 MBq 153Sm-EDTMP per kilogram of body weight. The activities for whole body, urinary bladder, and both thighs, as representative of soft tissue, were measured by region-of-interest technique. A background region of interest adjacent to the head was used to correct for bremsstrahlung. Bone uptake was calculated as initial whole-body activity minus urinary excretion and remaining soft-tissue activity. RESULTS: For 186Re-HEDP (n = 11) the mean bone uptake at 3 h after injection was 13.7% +/- 8.6% of initial whole-body activity. The remaining soft-tissue activity was 49.4% +/- 16.9%, and urinary excretion was 36.9% +/- 14.4%. At 24 h after injection, bone uptake reached a value of 21.8% +/- 9.0%. Urinary excretion increased to 65.3% +/- 12.8% according to a decreasing soft-tissue remainder activity of 12.8% +/- 5.4%. The corresponding results for 153Sm-EDTMP (n = 18) at 3 h after injection were 29.2% +/- 15.5% for bone uptake, 32.3% +/- 12.9% for urinary excretion, and 38.4% +/- 14.5% for soft tissue. At 24 h after injection, we calculated values of 47.7% +/- 11.2% for bone uptake, 39.5% +/- 13.8% for urinary excretion, and 12.7% +/- 4.7% for soft tissue. CONCLUSION: Bone uptake and soft-tissue retention for both 186Re-HEDP and 153Sm-EDTMP as obtained in this study agree well with the conventional 24-h whole-body retention measurements for these tracers. However, by this new scintigraphic quantification method, bone uptake and soft-tissue retention can be calculated separately, thus providing more detailed kinetic data and potentially improving the dosimetry of these radiopharmaceuticals in, for example, assessment of radiation dosage to bone and bone marrow.     

Can bone marrow scintigraphy predict platelet toxicity after treatment with 186Re-HEDP?

The toxicity of 186Re-1,1-hydroxyethylidene diphosphonate (186Re-HEDP) therapy in patients with painful bone metastases is mainly limited to thrombocytopaenia. The aim of this study was to investigate the influence of bone marrow scintigraphy on the prediction of decreased platelet counts after 186Re-HEDP therapy. Twenty-nine prostatic cancer patients with multiple painful bone metastases were included in the study. From a pre-therapy nanocolloid bone marrow scintigram, the bone marrow index (BMI) was determined as an indicator of the extent of bone marrow involvement. The influence of the BMI on the prediction of percent decrease in platelet counts was investigated. The mean BMI was 59 +/- 20. Regression analysis showed that the BMI does not improve the relationship between percent reduction in platelet count and administered dose. In contrast, we previously showed that the bone scan index (BSI) does predict the percent reduction in platelet counts before treatment. We conclude that bone marrow scintigraphy does not provide any additional information on platelet toxicity after a therapeutic dose of 186Re-HEDP. Bone scintigraphy is preferred in the prediction of reduced platelet counts.     

A practical guide to targeted therapy for bone pain palliation

Targeted radionuclide therapy is an effective and cost efficient treatment for multi-site metastatic bone pain. This paper discusses the physical characteristics of the licensed radiopharmaceuticals (153)Sm ethylenediamine-N,N,N',N'-tetrakis(methylene phosphonic acid) ((153)Sm-EDTMP), (186)Re 1,1-hydroxyethylidenediphosphonate ((186)Re-HEDP) and (89)SrCl(2) and considers the factors influencing treatment choice in specific clinical settings. The advantages and practical limitations of this approach are discussed, with emphasis on defining criteria for patient selection and response monitoring. Opportunities for future research and development are outlined.     

188Re—HEDP治疗肿瘤骨转移痛药代动力学研究

目的研究188Re标记的1-羟基-1,1-二膦酸钠乙烷（即依替膦酸盐,HEDP）在肿瘤骨转移患者体内的分布和排泄,分析不同剂量188Re—HEDP在患者体内的药代动力学特点。方法将40例肿瘤骨转移患者分为4组,每组10例,4组分别按体质量“弹丸”式经肘静脉注射188Re—HEDP20,30,40和50MBq／kg,给药时及给药后1,2,4,5,12,24,36,48,60和72h分别用SPECT仪采集胸前区和前后位、后前位全身图像,并收集患者尿液,测量放射性。利用感兴趣区（ROI）技术在左心室区测得经本底校正的放射性,作为血液放射性。将1h全身前位、后位放射性总计数率经死时间和时间衰减校正后的几何平均值设定为100％注射剂量（ID）,据此估算上述各时间点全身和各器官的百分注射剂量率（％ID）。各组间的计量资料采用元、中位数、范围等表示,组间比较采用方差分析或t检验。结果20～50MBq／kg范围内,188Re—HEDP在体内的时间-放射性曲线下面积（AUC）与其剂量呈线性关系,r^2=0．9376。4组均符合静脉给药二室模型,AUC值中位数分别为3．32×10^5,3．97×10^5,7．83×10^5,8．58×10^5;分布速度常数（α值）中位数分别为0．06,0．05,0．04,0．06;消除速度常数（B值）中位数分别为1．16×10^-3,1．16×10^-3,1．03×10^-3,1．15×10^-3;指数项系数A值中位数分别为3591．21,4858．23,5642．48,4167．05;指数项系数B值中位数分别为293．97,352．95,614．41,1063．82;药物分布相半衰期T1/2值中位数分别为12．51,12．83,15．41,12．02min;药物消除相半衰期T1／2（β）中位数分别为595．47,596．50,673．09,600．93min。骨组织是摄取188Re—HEDP的主要组织,给药后4h放射性摄取高,约为40％ID,其他组织未见明显摄取188Re—HEDP0188Re．HEDP主要通过泌尿系统排泄,给药后24h排出66．79％ID,其中74％在给药后5h内排出。结论20～50MBq／kg范围内,188Re—HEDP在机体内的药代动力学符合血管给药二室模型。188Re—HEDP T1/2（β）平均为616．50min。188Re—HEDP主要通过泌尿系统排泄;骨组织是摄取188Re—HEDP的主要组织。     

186Re-1,4,8,11-tetraaza cyclotetradecyl-1,4,8,11-tetramethylene phosphonic acid: a novel agent for possible use in metastatic bone-pain palliation

In connection with our work on the development of 186Re-tetra-phosphonates with optimum properties for use in bone pain palliation, a novel cyclic tetraphosphonate derivative, has been synthesized, complexed with 186Re and evaluated with promising results. The ligand, which consists of a cyclic array of tetra-aminomethylphosphonate groups, was synthesized using orthophosphorus acid, 1,4,8,11-tetraazacyclotetradecane and formaldehyde. The labeling conditions with 186Re have been standardized under varying reaction conditions to give maximum yield. In a reaction volume of 1 mL, maximum complexation yield of 98% was observed at pH 2 using 0.1 mg Re (37-370 MBq) for a ligand concentration at 9 x 10(-2) M/L, under heating at 100 degrees C for 30 min with 2 mg of stannous chloride. The complex was found to be stable for 6 days with RC purity remaining approximately 97%. The complex was characterized by paper chromatography in saline and acetone, wherein the R(f) exhibited were 0.9 and 0, respectively. Biodistribution studies of the complex were performed in male Wistar rats. Activity in femur which was observed to be 1.8%/g (equivalent to about 23% of the injected activity in skeleton) at 3 h post injection remained almost constant up to 48 h. Minimum activity was observed in blood and other soft tissues. The complex showed major renal clearance. Scintigraphic images in rabbits after injecting 70-100 MBq of 186Re-CTMP and using a dual head gamma camera were observed to be superior to 186Re-HEDP, prepared by a procedure standardized by us. Insignificant activity was observed in other vital organs. The results suggest the suitability of the complex for further evaluation in higher animals for bone pain palliation.     

Pharmacokinetics of rhenium-186 after administration of rhenium-186-HEDP to patients with bone metastases.

The pharmacokinetics of 186Re-HEDP, a radiopharmaceutical for palliative treatment of metastatic bone pain, was investigated in 11 patients (17 studies) who suffered from metastatic breast or prostate cancer. Half-life times of 186Re in three blood fractions (whole blood, plasma and plasma water) were 40.1 +/- 5.0, 41.0 +/- 6.0 and 29.5 +/- 6.4 hr, respectively. Time-dependent increase in plasma-protein binding was observed, probably caused by in vivo decomposition of 186Re-HEDP. Total urinary 186Re excretion was 69% +/- 15%, of which 71% +/- 6% was excreted in the first 24 hr after injection. The BSI (i.e., fraction of the skeleton showing scintigraphic evidence of metastatic disease) closely correlated with the fraction of dose non-renally cleared (r = 0.98). This implies that the amount of radioactivity taken up by the skeleton and hence the bone marrow absorbed dose can be predicted from a diagnostic pre-therapy 99mTc-HDP scintigram. The pharmacokinetic behavior indicates that 186Re-HEDP has suitable properties to justify its application.     

A phase 2 study of high-activity 186Re-HEDP with autologous peripheral blood stem cell transplant in progressive hormone-refractory prostate cancer metastatic to bone

Purpose We investigated the potential for improvement in disease control by use of autologous peripheral blood stem cell transplant (PBSCT) to permit administration of high activities of ¹⁸⁶Re-hydroxyethylidene diphosphonate (HEDP) in patients with progressive hormone-refractory prostate cancer (HRPC). Methods Eligible patients had progressive HRPC metastatic to bone, good performance status and minimal soft tissue disease. Patients received 5,000 MBq of ¹⁸⁶Re-HEDP i.v., followed 14 days later by PBSCT. Response was assessed using PSA, survival, pain scores and quality of life. Results Thirty-eight patients with a median age of 67 years (range 50–77) and a median PSA of 57 ng/ml (range 4–3,628) received a median activity of 4,978 MBq ¹⁸⁶Re-HEDP (range 4,770–5,100 MBq). The most serious toxicity was short-lived grade 3 thrombocytopenia in 8 (21%) patients. The median survival of the group is 21 months (95%CI 18–24 months) with Kaplan-Meier estimated 1- and 2-year survival rates of 83% and 40% respectively. Thirty-one patients (81%, 95% CI 66–90%) had stable or reduced PSA levels 3 months post therapy while 11 (29%, 95% CI 15–49%) had PSA reductions of >50% lasting >4 weeks. Quality of life measures were stable or improved in 27 (66%) at 3 months. Conclusion We have shown that it is feasible and safe to deliver high-activity radioisotope therapy with PBSCT to men with metastatic HRPC. Response rates and survival data are encouraging; however, further research is needed to define optimal role of this treatment approach.     

Development of a novel 99mTc-chelate-conjugated bisphosphonate with high affinity for bone as a bone scintigraphic agent.

In bone scintigraphy using (99m)Tc with methylenediphosphonate ((99m)Tc-MDP) and hydroxymethylenediphosphonate ((99m)Tc-HMDP), it takes 2-6 h after an injection before imaging can start. This interval could be shortened with a new radiopharmaceutical with higher affinity for bone. Here, based on the concept of bifunctional radiopharmaceuticals, we designed a (99m)Tc-mercaptoacetylglycylglycylglycine (MAG3)-conjugated hydroxy-bisphosphonate (HBP) ((99m)Tc-MAG3-HBP) and a (99m)Tc-6-hydrazinopyridine-3-carboxylic acid (HYNIC)-conjugated hydroxy-bisphosphonate ((99m)Tc-HYNIC-HBP). METHODS: (99m)Tc-MAG3-HBP was prepared by complexation of MAG3-HBP with (99m)Tc using SnCl(2) as a reductant. The precursor of (99m)Tc-HYNIC-HBP, HYNIC-HBP, was obtained by deprotection of the Boc group after the coupling of Boc-HYNIC to a bisphosphonate derivative. (99m)Tc-HYNIC-HBP was prepared by a 1-pot reaction of HYNIC-HBP with (99m)TcO(4)(-), tricine, and 3-acetylpyridine in the presence of SnCl(2). Affinity for bone was evaluated in vitro by hydroxyapatite-binding assays for (99m)Tc-HMDP, (99m)Tc-MAG3-HBP, and (99m)Tc-HYNIC-HBP. Biodistribution experiments for the 3 (99m)Tc-labeled compounds were performed on normal rats. RESULTS: (99m)Tc-MAG3-HBP and (99m)Tc-HYNIC-HBP were each prepared with a radiochemical purity of >95%. In the in vitro binding assay, (99m)Tc-MAG3-HBP and (99m)Tc-HYNIC-HBP had greater affinity for hydroxyapatite than (99m)Tc-HMDP. In the biodistribution experiments, (99m)Tc-MAG3-HBP and (99m)Tc-HYNIC-HBP had higher levels of radioactivity in bone than (99m)Tc-HMDP. (99m)Tc-MAG3-HBP was cleared from the blood slower than (99m)Tc-HMDP, whereas there was no significant difference in clearance between (99m)Tc-HYNIC-HBP and (99m)Tc-HMDP. Consequently, (99m)Tc-HYNIC-HBP showed a higher bone-to-blood ratio than (99m)Tc-HMDP. CONCLUSION: We developed a novel (99m)Tc-chelate-conjugated bisphosphonate with high affinity for bone and rapid clearance from blood, based on the concept of bifunctional radiopharmaceuticals. The present findings indicate that (99m)Tc-HYNIC-HBP holds great potential for bone scintigraphy.     

肿瘤骨转移疼痛患者对^188Re-HEDP的耐受性研究

目的 评价^188Re-1-羟基-1,1-二膦酸钠乙烷（即依替膦酸盐,HEDP）治疗肿瘤骨转移疼痛患者的安全性.方法 符合入选标准的31例患者（前列腺癌10例,乳腺癌9例,肺癌3例,肝癌5例,直肠癌2例,食管癌1例,肾癌1例,均随时间顺序人选）知情同意后接受了按体质量肘静脉单次注射^188ReHEDP,据药物递增剂量分为4个组：20 MBq/kg组6例、30 MBq/kg组6例、40 MBq/kg组9例、50 MBq/kg组10例.低剂量组安全性分析结束并显示安全后,才开始下一剂量组试验.如果患者出现由于用药引起的不可耐受的、WHO公布的Ⅲ或Ⅳ级骨髓毒性,即终止剂量递增,并认为前一组剂量为最大可接受剂量.观察指标包括给药前及给药后8周内每例患者的生命体征（用药后1,6,12,24,48,72 h和1,2,3,4,6,8周）,血细胞计数（用药后1,2,3,4,6和8周）,心电图,肝、肾功能,ALP（用药后4,8周）,＂反跳痛＂以及不良反应等.统计分析主要针对符合方案集（PP）人群,包括统计描述和统计推断（t检验）.结果 31例患者中有27例属于PP人群：20 MBq/kg组5例、30 MBq/kg组5例、40 MBq/kg组8例、50 MBq/kg组9例.在受试剂量范围内,没有观察到188Re-HEDP对患者生命体征、心电图、肝肾功能和ALP的不良影响.20 MBq/kg组的5例患者中仅1例自细胞出现WHO Ⅰ级毒性;30 MBq/kg组5例患者中2例白细胞出现WHO Ⅰ级毒性,其中1例合并血小板Ⅲ级毒性,但给药后8周白细胞和血小板均恢复正常;40 MBq/kg组8例患者中2例白细胞和血小板同时出现毒性反应,分别为WHO Ⅰ级和Ⅱ级,表现为白细胞和血小板同时、同级减低;50 MBq/kg组9例患者中3例白细胞出现WHOⅡ级毒性.全部患者的血小板均在给药后4周达最低水平,平均为143.5×109/L;白细胞均在给药后6周达最低水平,平均为5.4×109/L（两者与给药前基线值比较,t值分别为3.1325和3.3156,P均＜0.05）,给药后8周自细胞和血小板均恢复到基线水平;而血红蛋白在给药后8周最低（与基线值比较,t值为3.4917,P＜0.05）.PP人群27例中有2例出现＂反跳痛＂,发生率7.41%（2/27）.结论 按体质量注射188Re-HEDP 20,30,40和50 MBq/kg对肿瘤骨转移患者均无明显毒性及不良反应,且随着用药剂量增加,188Re-HEDP对骨髓的抑制有增加趋势.