Evaluation of stannous oxidation in the preparation of ultrahigh-purity 99m Tc(V)-DMSA

It has been shown previously that renal kit, trivalent technetium-99m dimercaptosuccinic acid [99mTc(III)-DMSA], can be transformed into tumour imaging agent, pentavalent technetium-99m DMSA [99mTc(V)-DMSA], by adding sodium bicarbonate (NaHCO3) and subsequently bubbling with oxygen. However, the purity of this pentavalent preparation was reported to be in the range 83-94% at best. In this study, the preparation of ultrahigh-purity 99mTc(V)-DMSA is described, and the role of stannous oxidation in the conversion of 99mTc(III)-DMSA to 99mTc(V)-DMSA is evaluated in order to understand the underlying mechanism. The results show that controlled oxygen bubbling increases the 99mTc(V)-DMSA levels, with a concomitant decrease in the 99mTc(III)-DMSA levels, in a time-dependent pattern. The purity of the pentavalent DMSA is shown to be consistently very high (>99%), as estimated by chromatography, and this correlates very well with the minimal or no renal uptake of this compound in patient studies.     

Preparation and evaluation of 99mTc(V)-DMSA complex: Studies in medullary carcinoma of thyroid

Consequent to the promising results reported with ^99mTc(V)-DMSA for imaging certain types of soft tissue tumors, we have developed methods to prepare this radiopharmaceutical in three ways:-(i) from freshly prepared reagents, (ii) through the use of a two component kit and (iii) use of the standard renal DMSA kit by a modified recipe. The ^99mTc(V)-DMSA complex has been subjected to paper electrophoretic and chromatographic procedures and also biodistribution studies. The distinctly different behaviour of this new product compared to that of the well known renal DMSA complex has been clearly established. Scintiimaging in a preliminary clinical trial in patients with medullary carcinoma of the thyroid has been encouraging.     

Novel tumortropic ester derivatives of 99mTc(V) mesodimercapto succinic acid with low affinity for bone tissue

Starting from our previous finding that 99mTc(V) dimercaptosuccinic acid (99mTc(V)-DMSA), a useful agent for the localization of osteosarcoma and bone metastases, loses its bone affinity when one ester group is introduced into the complex we studied the impact of esterification in more detail. This paper reports on the evaluation of various ester complexes of 99mTc(V)-DMSA in rats and tumour-bearing nude mice with regard to their tumour retention and improvement of the tumour to tissue ratios. The distribution patterns of the complexes [99mTcO(DMSA)2]- (A), [99mTcO(DMSA/DMSEt)]- (B) and [99mTcO(DMSEt)2]- (C) are gradually changed with the number of ester groups in the anionic complex. However, the asymmetric diester complex [99mTcO(DMSA/DMSEt2)]- (D) is very slowly cleared, especially from the blood of nude mice. Moreover, this complex differs significantly from the symmetrical complex C in its elimination behaviour from the liver and kidneys. The tumour uptake is maintained with complexes that contain one or two non-hydrolysable ester functions. Preliminary biodistribution studies of the monoethyl and diethyl ester complexes B, C and D in comparison with A in tumour-bearing nude mice showed similar uptake into the human squamous cell carcinoma (FaDu) as well as into the human colonic cell carcinoma (HT29) of nude mice. The low bone accumulation of B, C and D results in excellent tumour-to-bone ratios, e.g., approx. 3:1 for the ester complex B compared to approx. 1:2 for complex A. Differences were observed in the accumulation and elimination behaviour of the complexes A and B in various bone structures of rats. The age-dependent uptake of A and B was compared in long bone (femur) and in cranial bone of rats. The results suggest that 99mTc(V)-DMSA complexes that contain a functional ester, and their 188Re analogues, may be superior to 99mTc(V)/188Re(V)-DMSA in diagnostic and therapeutic nuclear medicine.     

Positive imaging of cardiomyopathy with99mTc(V)-DMSA

A case of histologically proven dilated cardiomyopathy and a case of clinically diagnosed cardiomyopathy (cardiac amyloidosis was strongly suspected but was not confirmed) were examined with 99mTc(V)-dimercaptosuccinic acid (DMSA). 99mTc(V)-DMSA accumulation in the damaged myocardium was clearly demonstrated. These results suggested the possibility that 99mTc(V)-DMSA could be used as a positive agent for cardiomyopathy.     

Preparation of [186Re]Re-DMSA and its bio-distribution studies.

99mTc(V)-DMSA is widely used for imaging medullary carcinoma and hence 186/188Re(V)-DMSA is suggested as a potential agent for treating medullary carcinoma. In the present paper, we report the work carried out for the preparation of [186Re]Re(V)-DMSA and it's bio-distribution studies in Wistar rats. The complex was prepared by reducing 186Re (100 micrograms, 0.54 microM, approximately 150 MBq) in the presence of DMSA (2 mg, 11 microM) with stannous chloride (0.4 mg, 2.2 microM) in acidic medium at pH 2. The reaction was taken to completion by heating the complex in a boiling water bath for 30 min. Bio-distribution studies carried out revealed that pharmacological behaviour of 186Re(V)-DMSA is similar to that of 99mTc(V)-DMSA except that the kidney uptake is marginally higher. The kidney uptake reduced significantly when the pH of the complex was adjusted to 8 prior to injection. The in vitro stability studies of this complex suggest that the product formed is stable and could be used for clinical trials.     

Analogy between tumor uptake of technetium(V)-99m dimercaptosuccinic acid (DMSA) and technetium-99m-MDP

Sixty patients with a variety of malignant tumors were examined with Tc-99m(V) dimercaptosuccinic acid (DMSA) prepared by modification of a commercially available DMSA kit. Significant uptake of Tc-99m(V)-DMSA was observed in a number of tumors, offering additional clinically useful information. In the majority of cases in this study, however, the benefit of the Tc-99m(V)-DMSA image was limited because of low sensitivity. The most striking observation was the similarity between the tumor concentration of Tc-99m(V)-DMSA and the Tc-99m-MDP uptake in the tumor on the regular bone image. Therefore, patients with Tc-99m-MDP uptake in nonosseous tumor sites on the bone scan may be suitable candidates for tumor imaging with Tc-99m(V)-DMSA.     

The role of 99mTc(V)-DMSA scan as compared to 99mTc-MDP and CT scans in imaging the primary tumor and metastases of osteosarcoma

The oncophilic complex of technetium-99m labeled pentavalent dimercaptosuccinic acid (99mTc(V)-DMSA) has been successfully used for the detection of primary and metastatic medullary thyroid cancer and for imaging various soft tissue tumors like lung, brain and prostate cancer. In this article, the role of 99mTc(V)-DMSA in the diagnosis of the primary tumor and metastases of osteosarcoma patients as compared to the 99mTc-MDP scan and the CT scan was studied. Twenty-eight patients with bone disease were referred to the Nuclear Medicine Department of Saint Savas Oncology Hospital in Athens from the Orthopedics Department of the same Hospital. From them, 18 (Group A) had osteosarcoma, 7 (Group B) osteomyelitis and 3 (Group C) bone fractures. The final diagnosis was made after fine needle aspiration biopsy. All patients were subjected to the 99mTc(V)-DMSA scan, the standard bone scan (99mTc-MDP) and CT scan. Group A patients showed a selective uptake of 99mTc(V)-DMSA in the primary tumor region. No abnormal 99mTc(V)-DMSA uptake was observed in the patients of Groups B and C. The 99mTc(V)-DMSA scan was found to be superior to the 99mTc-MDP and the CT scans in identifying metastases of osteosarcoma. Sensitivity was 100%, 86% and 98% respectively.     

Pentavalent technetium-99m (V)-DMSA uptake in a pheochromocytoma in a patient with Sipple's syndrome

This case report describes 99mTc(V)-dimercaptosuccinic acid (DMSA) accumulation in a pheochromocytoma in a patient with Sipple's syndrome. Scintigraphy with 99mTc(V)-DMSA demonstrated uptake in medullary carcinoma of the thyroid gland (MCT). Iodine-131 metaiodobenzylguanidine (MIBG) scintigraphy showed the bilateral pheochromocytomas but did not demonstrate uptake in the MCT.     

Pitfalls in scintigraphic detection of neuroendocrine tumours.

We report 4 cases of abnormal results using iodine-123 metaiodobenzylguanidine (123I-mIBG) or technetium-99m (V) dimercaptosuccinic acid (99mTc(V)-DMSA) scintigraphy in the diagnosis and follow-up of presumed neuroendocrine tumours. The present series consisted of 2 false-positive cases (1 adenomatous polyp of the caecum with mIBG and 1 follicular adenoma of the thyroid with DMSA) and 2 cases of anomalous uptake of (V)-DMSA in a non-neuroendocrine tissue.     

A comparison of the tumor-seeking agent Tc-99m(V) dimercaptosuccinic acid and the renal imaging agent Tc-99m dimercaptosuccinic acid in humans

Being aware of the ideal nuclear properties of Tc-99m, our interest has been focused on the design of the (+5) oxidation state Tc-99m(V) dimercaptosuccinic acid (Tc(V)-DMSA) as a tumor-seeking agent. Tc-99m(V) DMSA holds a TcO4(3-) core and, like PO4(3-), has excellent characteristics for tumor uptake, but has a different distribution than the well-known renal scanning agent, Tc-99m DMSA. The differences in chemical behavior of Tc-99m(V) DMSA and Tc-99m DMSA are discussed. Three cases in which neoplasms were studies with Tc-99m(V) DMSA and Tc-99m DMSA are presented. Tc-99m DMSA and Tc-99m(V) DMSA, having a common ligand and tracer but, with the metal ion core in a different oxidation state, the uptake characteristics are altered markedly.     

99mTc(V)DMSA quantitatively predicts 188Re(V)DMSA distribution in patients with prostate cancer metastatic to bone

Rhenium-188 dimercaptosuccinic acid complex [188Re(V)DMSA], a potential therapeutic analogue of the tumour imaging agent 99mTc(V)DMSA, is selectively taken up in bone metastases in patients with prostate cancer. It would be helpful in planning palliative radionuclide therapy if 99mTc(V)DMSA could be used to predict tumour and kidney retention of 188Re(V)DMSA. The aim of this study was to determine the correlation between tumour-to-normal tissue ratios and kidney-to-soft tissue ratios of 99mTc(V)DMSA and 188Re(V)DMSA. This would determine whether a scan with 99mTc(V) DMSA could be used to identify patients for whom 188Re(V)DMSA treatment would be contra-indicated, and enable prediction of relative kidney and tumour radiation absorbed dose in 188Re(V)DMSA treatment. Ten patients with prostate carcinoma were recruited following observation of disseminated bone metastases on a recent 99mTc-hydroxydiphosphonate bone scan. Whole-body planar scans were obtained at ca. 4 h and 24 h after hydration and injection of 600 MBq 99mTc(V)DMSA, and a week later, at similar times after hydration and injection of 370 MBq 188Re(V)DMSA. A triple-energy window (TEW) scatter correction was applied to the 188Re scans. Counts per pixel were determined in regions of interest drawn over metastatic sites, kidneys and normal soft tissue. Tumour-to-soft tissue ratios were significantly lower (by a factor of approximately 0.8 after the TEW was applied) on 188Re scans than on 99mTc scans, but the two were highly linearly correlated both in all individual patients and in tumours pooled from all patients together both at 4 h and at 24 h. Kidney-to-soft tissue ratios were similarly correlated and were lower for 188Re than for 99mTc by a similar factor. Both tumour- and kidney-to-soft tissue ratios increased between 4 and 24 h but the latter increased more. In conclusion, only minor differences were seen between 99mTc and 188Re scans, and kidney-to-background ratios on 188Re scans were not higher than on 99mTc scans. These differences are insufficient to infer that they are due to a real difference in biodistribution, and they may be due only to different physical imaging characteristics. Thus 99mTc(V)DMSA scans are predictive of 188Re(V)DMSA biodistribution and could be used to estimate tumour and renal dosimetry and assess suitability of patients for 188Re(V)DMSA treatment.     

^99mTc（V）—DMSA骨显像诊断骨转移瘤的临床价值

目的：评价99mTc（V）－DMSA显像在骨转移瘤诊断中的意义。材料和方法：对91例疑骨转移瘤患者行99mTc（V）DMSA全身显像，并与99mTc-MDP全身骨显像及其它检查对比。结果：74例证实存在骨转移瘤者，99mTc．MDP骨显像均显示异常放射性浓聚，99mTc（V）-DMSA显像72例显示了与99mTc-MDP显像某些相同部位的放射性浓聚，2例99mTc（V）DMSA显像阴性。17例骨良性病变，99mTc－MDP骨显像显示轻度异常放射性浓聚，而99mTc（V）-DMSA显像却未见异常的放射性浓聚。结论：99mTc（V）－DMSA诊断骨转移瘤的特异性比99mTc-MDP骨显像高，在骨良恶性肿瘤鉴别诊断中具有重要的临床价值。     

Renal handling of technetium-99m DMSA: evidence for glomerular filtration and peritubular uptake

The finding of an enhanced excretion of [99mTc]dimercaptosuccinic acid (DMSA) in patients with tubular reabsorption disorders prompted us to investigate the role of filtration in the renal handling of [99mTc]DMSA. Our studies in human serum indicated that binding to serum proteins was approximately 90%. Chromatography of human urine and studies in rats showed that the complex was excreted unaltered into the urine. Renal extraction of [99mTc]DMSA in a human volunteer was 5.8%. Continuous infusion of [99mTc]DMSA in 13 individuals with normal renal function gave the following results (mean +/- s.d.): plasma clearance of [99mTc]DMSA 34 +/- 4 ml/min, urinary clearance of [99mTc]DMSA 12 +/- 3 ml/min. The calculated filtered load of [99mTc]DMSA closely resembled the urinary clearance, whereas the plasma clearance was about three times faster. This indicates that peritubular uptake accounts for approximately 65% and filtration for approximately 35% of the renal handling of [99mTc]DMSA.     

99mTc(V)-DMSA SPECT for the assessment of disease activity in Graves' ophthalmopathy

OBJECTIVE: The aim of this study was to evaluate the use of 99mTc(V)-dimercaptosuccinic acid (99mTc(V)-DMSA) scintigraphy for the assessment of disease activity in patients with Graves' ophthalmopathy (GO) and compare their clinical parameters. METHODS: The study involved 20 patients who were clinically inactive and eight patients who were clinically active, a total 28 GO patients (18 female, 10 male; mean age: 39.2+/-13.4 years) and 12 control subjects (six female, six male; mean age: 57.12+/-12 years). Planar and SPECT orbital images were obtained 4 h after the intravenous injection of 555-740 MBq 99mTc(V)-DMSA, using low-energy, high-resolution, parallel-hole collimators with dual-head detectors. All SPECT data were reconstructed on conventional axial, sagittal and coronal projections using an iterative reconstruction. Semi-quantitative evaluation was performed comparing the orbital activity with nasal activity based on four grades. GO was classified according to the NOSPECS classification of the American Thyroid Association. Disease was considered clinically active if symptoms and signs deteriorated over 3 months. RESULTS: No significant correlation was detected between clinical activity and classification (P=0.192). However, clinical activity and 99mTc(V)-DMSA uptake were significantly correlated (P=0.0001). There was no correlation between the clinical classification and scintigraphic grading. Bilateral orbital index of the active group was significantly higher than that of the inactive group (P=0.0001). CONCLUSION: 99mTc(V)-DMSA imaging discriminates the active from inactive GO as well as showing an ongoing subclinical inflammation in the orbits of the patients with GO, regardless of the disease activity clinically. Our results revealed that 99mTc(V)-DMSA is a promising agent for the diagnosis of active Graves' ophthalmopathy.     

Active inflammatory bowel disease: head-to-head comparison between 99mTc-hexamethylpropylene amine oxime white blood cells and 99mTc(V)-dimercaptosuccinic acid scintigraphy

PURPOSE: Evaluation and comparison between pentavalent 99mTc dimercaptosuccinic acid (99mTc(V)-DMSA) and 99mTc-hexamethylpropylene amine oxime white blood cell (99mTc-HMPAO WBC) scintigraphy in the detection and assessment of disease activity in patients with active inflammatory bowel disease (IBD). MATERIALS AND METHODS: 99mTc(V)-DMSA scintigraphy was performed in 23 patients with active IBD and true positive 99mTc-HMPAO WBC scintigraphy. Images were considered positive when an area of increased uptake was observed. To assess severity of IBD, semi-quantitative analysis was included with reference to the uptake in the iliac crest. Comparison with endoscopic, radiological and clinical data was performed. RESULTS: The diagnostic accuracy of 99mTc-HMPAO WBC and 99mTc(V)-DMSA was 91% and 84%, respectively. A significant correlation between the findings of both radioisotopic methods and scintigraphy score was demonstrated. Endoscopic findings were significantly correlated with scintigraphic results. Kappa statistics showed a moderate to good agreement between the two scintigraphic methods. Two patients (8.8%) had negative findings with 99mTc(V)-DMSA scintigraphy (false negative results). CONCLUSION: 99mTc(V)-DMSA compared to 99mTc-HMPAO WBC could provide a simple, non-invasive alternative method for the assessment of disease activity, although it is slightly inferior to 99mTc-HMPAO WBC scintigraphy especially in the evaluation of disease localization in IBD patients.     

A convenient method for the preparation of 99mTc(V)dimercaptosuccinic acid (99mTc(V)-DMSA)

Tc(IV)-DMSA for kidney scintigraphy has been prepared in acidic solution. Once the labeling is done in basic solution, upon addition of a small amount of NaHCO3, a mixture of 3-4 other DMSA-complexes is formed, presumably containing Tc(V). Kidney uptake in male adult rats of the 99mTc(V)-DMSA is 1.6% injected dose/g (4.9%/total organ) compared to 16.4% injected dose/g (resp. 50.3%/total organ) for 99mTc(IV)-DMSA.     

Use of 99mTc (V) DMSA scintigraphy in the detection and localization of intestinal inflammation: comparison of findings and colonoscopy and biopsy

PURPOSE: To evaluate the potential use of technetium 99m (99mTc) (V) dimercaptosuccinic acid (DMSA) scintigraphy in the detection and localization of intestinal inflammation. MATERIALS AND METHODS: In a prospective study, 62 patients who were suspected of having intestinal inflammation and 30 control subjects were enrolled. All patients underwent 99mTc (V) DMSA scintigraphy and colonoscopy with biopsy within 1 week. 99mTc (V) DMSA scintigrams were interpreted blindly with respect to clinical information, and radiotracer uptake in the bowel segments was graded. The findings were then compared with the results of the colonoscopy and colonoscopic biopsy. RESULTS: In the detection of intestinal inflammation, findings at 99mTc (V) DMSA scintigraphy were as follows: true-positive in 55, false-positive in two, true-negative in 32, and false-negative in three. Overall sensitivity was 95%; overall specificity, 94%; and overall accuracy, 95%. CONCLUSION: Our results show that 99mTc (V) DMSA scintigraphy is a useful noninvasive diagnostic test for the detection and localization of intestinal inflammation.     

99mTc(V)-DMSA and99mTc-MDP uptake and no67Ga-citrate uptake in a case of primary pulmonary leiomyosarcoma

Tumor scintigraphy with 67Ga-citrate, 99mTc(V)-DMSA and 99mTc-MDP were performed on a patient with rare primary pulmonary leiomyosarcoma. While 67Ga-citrate accumulation to the tumor was not recognized, 99mTc(V)-DMSA and 99mTc-MDP scintigraphy showed relatively intense localization of the tracers in the lesion, and were very useful in suggesting the characteristics of the tumor.     

99mTc renal tubular function agents: current status

Orthoiodohippuric (OIH) acid labeled with 131I is a widely used renal radiopharmaceutical agent and has been the standard radiopharmaceutical agent for the measurement of effective renal plasma flow (EPRF). Limitations to the routine clinical use of 131I OIH are related to the suboptimal imaging properties of the 131I radionuclide and its relatively high radiation dose. 123I has been substituted for 131I; however, its high cost and short shelf-life have limited its widespread use. Recent work has centered on the development of a new 99mTc renal tubular function agent, which would use the optimal radionuclidic properties and availability of 99mTc and combine the clinical information provided by OIH. The search for a suitable 99mTc renal tubular function agent has focused on the diamide dithiolate (N2S2), the paraaminohippuric iminodiacetic acid (PAHIDA), and the triamide mercaptide (N3S) donor ligand systems. To date, the most promising 99mTc tubular function agent is the N3S complex: 99mTc mercaptoacetyltriglycine (99mTc MAG3). Studies in animal models in diuresis, dehydration, acid or base imbalance, ischemia, and renal artery stenosis demonstrate that 99mTc MAG3 behaves similarly to 131I OIH. A simple kit formulation is available that yields the 99mTc MAG3 complex in high radiochemical purity. Studies in normal subjects and patients indicate that 99mTc MAG3 is an excellent 99mTc renal tubular agent, but its plasma clearance is only 50% to 60% that of OIH. In an effort to develop an improved 99mTc renal tubular function agent, changes have been made in the core N3S donor ligand system, but to date no agent has been synthesized that is clinically superior to 99mTc MAG3.     

Mechanism of renal concentration of technetium-99m glucoheptonate

Seventy female Sprague-Dawley rats were studied to determine the mechanism of tubular localization and the effects of commonly encountered changes in hydration and acid-base balance on renal uptake and urinary excretion of technetium-99m glucoheptonate ([99mTc]GHA). The in-vivo protein binding and protein-free plasma clearance of [99mTc]GHA also were quantitated. Twenty additional rats were studied to determine the effects of PAH competition and probenecid blockade on renal uptake of [99mTc]dimercaptosuccinic acid (DMSA) in comparison with their effects on [99mTc]GHA localization. Kidney uptake of [99mTc]GHA averaged 11.17 +/- 0.49 (s.e.)% of the injected dose in control animals. This varied slightly among groups but was significantly reduced by probenecid blockade and para-aminohippuric acid (PAH) competition to 4.08 +/- 0.55 (p less than 0.005) and 2.39 +/- 0.14 (p less than 0.005), respectively. Technetium-99m DMSA was not affected in its renal accumulation by these maneuvers. The total plasma clearance of [99mTc]GHA was lower than iodine-125(125I)iothalamate but the clearance of the protein free supernate was higher, raising a possibility of some tubular secretion. Acidification of the urine which has been shown to reduce [99mTc]DMSA uptake appeared to have no effect on [99mTc]GHA. Hepatic uptake was minimal in all groups averaging less than 1% injected dose. These data demonstrate that renal accumulation of [99mTc]GHA is blocked by probenecid and PAH suggesting that it is actively concentrated in the proximal tubule by enzyme systems similar to those involved in PAH and hippuran transport. It appears that [99mTc]GHA uptake measures a different aspect of kidney function than [99mTc]DMSA.