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.     

Imaging of soft tissue tumors with Tc(V)-99m dimercaptosuccinic acid. A new tumor-seeking agent

Tumor scintigraphy, using Tc(V)-99m dimercaptosuccinic acid (Tc(V)-DMS) was performed in 58 patients with soft tissue tumors, and the results were compared with that of Ga-67 citrate. Tc(V)-DMS was found to have a sensitivity of 90% for malignant tumors including aggressive fibromatosis compared to that of Ga-67 citrate, which was 56%. However, the specificity of Tc(V)-DMS for these tumors was 71% but with Ga-67 citrate the specificity was 80%. The imaging accuracy in soft tissue tumors with Tc(V)-DMS and Ga-67 citrate was 78% and 71%, respectively. Although the accumulation of Tc(V)-DMS has been detected in some benign soft tissue tumors, the reduced accumulation in inflammatory lesions compared to Ga-67 citrate was recognized, and Tc(V)-DMS could be of great use in the detection of extension or location of malignant soft tissue tumors.     

Is ECT imaging with Tc(V)-99m dimercaptosuccinic acid useful to detect lung metastases of osteosarcoma?

ECT imaging, using Tc(V)-99m dimercaptosuccinic acid [Tc(V)-DMS] was performed in two patients with lung metastasis of osteosarcoma, and the results were compared with those of CT scan. Clear accumulation of Tc(V)-DMS was recognized in all cases in the same area that CT scans demonstrated. Tc(V)-DMS was labeled under optimal pH 8, had very low SnCl2 concentrations, an equilibrium between a stable form and a dissociated form of anion TcO4(3-) structurally similar to PO4(3-), and was postulated for tumor uptake. Considering this proposed mechanism for Tc(V)-DMS uptake by tumor cells, ECT imaging using this tracer could be of use in the early detection of lung metastasis of osteosarcoma.     

Preparation and clinical evaluation of technetium-99m dimercaptosuccinic acid for tumour scintigraphy

We describe a simple method of pentavalent technetium-99m dimercaptosuccinic acid [^99mTc(V)-DMSA] preparation for the imaging of medullary carcinoma of the thyroid using commercially available kits. ^99mTc(V)-DMSA is available at high pH (approximately 7.5) by adding NaHCO₃ solution in the presence of a small amout of reducing agent (SnCl₂). On the other hand, trivalent ^99mTc-DMSA [^99m-Tc(III)-DMSA] can be obtained at low pH (below 3) in the presence of an excess amount of reducing agent. In the clinical evaluation of a patient with a medullary carcinoma of the thyroid, only ^99mTc(V)-DMSA revealed an area of intense accumulation.     

Visualization of orbital retinoblastoma with technetium-99m (V) dimercaptosuccinic acid

The potential contributions of technetium-99m (V) dimercaptosuccinic acid scintigraphy in the evaluation of orbital retinoblastoma, its local extensions and metastases were assessed in this study. Both planar and SPECT images clearly demonstrated the primary tumor and metastatic sites. Following confirmation of our results by contemporaneous ultrasonography, MRI and a subsequent incisional biopsy, the patient was treated with external beam radiotherapy and chemotherapy. This preliminary study showed that in combination with other diagnostic tests, Tc-99m (V) DMSA scintigraphy may play a role in the detection and follow-up of the local tumor extensions and metastases in patients with retinoblastoma.     

Visualization of uveal amelanotic melanoma with technetium-99m(V) dimercaptosuccinic acid

The possibility of using technetium-99m(V) dimercaptosuccinic acid, Tc-99m DMSA, in the evaluation of uveal amelanotic melanoma was assessed in this study. Both planar and SPECT images clearly demonstrated the tumor. Following confirmation of our results by contemporaneous ultrasonography and MRI the patient was treated with Iodine-125 brachytherapy. In combination with other diagnostic tests, Tc-99m(V) DMSA scintigraphy may play a role in the detection of uveal melanoma and its possible systemic metastases.     

In vitro adsorption of 99Tc(m)-MIBI, 99Tc(m)-tetrofosmin, 99Tc(m)-furifosmin and 99Tc(m)O4- onto tubes

Adsorption of radiopharmaceuticals onto disposable syringes has been reported to amount to levels of almost 50%. Data on adsorption of radiopharmaceuticals onto materials used for in vitro studies are extremely limited. We assessed the extent of adsorption of 99Tc(m) hexakis(2-methoxyisobutylisonitrile) (99Tc(m)-MIBI), 99Tc(m)-tetrofosmin, 99Tc(m)-furifosmin and 99Tc(m)O4 onto tubes used for in vitro measurement of cellular uptake of these radiopharmaceuticals. The influence on adsorption of different incubation media, temperature and time of incubation was evaluated. Total (not corrected for adsorption) uptake was compared with corrected, net cellular uptake in SK-BR-3, MCF-7 and liposarcoma cell lines. Values of adsorption ranging from 0.94+/-0.13% to 7.07+/-0.46% were found. The extent of adsorption of all the radiopharmaceuticals varied with the type of incubation medium and the incubation temperature. With 99Tc(m)-furifosmin, adsorption was dependent on the incubation time as well on the incubation temperature and some of the incubation media investigated. Our findings indicate that systematic investigations to evaluate the adsorption of radiopharmaceuticals onto materials used during in vitro studies of cellular uptake should be considered a mandatory aspect of quality control.     

心肌灌注显像剂99Tcm-Q3的研制

目的研制新型心肌灌注显像剂９９ＴｃｍＮ,Ｎ′亚乙基二（乙酰丙酮亚胺）二［三（３甲氧基１丙基）膦］（简称Ｑ３）。方法合成显像剂的配体Ｎ,Ｎ′亚乙基—二（乙酰丙酮亚胺）和三（３甲氧基１丙基）膦后,用ＳｎＣｌ２·２Ｈ２Ｏ在强碱性条件下,还原９９ＴｃｍＯ－４标记Ｎ,Ｎ′亚乙基—二（乙酰丙酮亚胺）,再加入三（３甲氧基１丙基）膦反应１０ｍｉｎ,制得９９ＴｃｍＱ３。进行９９ＴｃｍＱ３小鼠体内分布和家兔显像实验,以及体外稳定性和急性毒性实验。结果９９ＴｃｍＱ３的心肌摄取快,摄取率高,注射后５ｍｉｎ时每克心肌组织的摄取约为注射剂量的２４６６％,滞留时间长,注射后４ｈ心肌清除不明显;血液、肺、肝脏清除均快。该显像剂无毒副作用,稳定性达６ｈ以上。结论９９ＴｃｍＱ３是提高心肌灌注显像质量的较理想的显像剂。     

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.     

Synthesis and biodistribution of a new (99m)Tc nitrido complex for cerebral imaging

The bis(N-isopentyl dithiocarbamato) nitrido technetium-99m complex [(99m)TcN(IPEDTC)(2)] (IPEDTC: N-isopentyl dithiocarbamato) has been synthesized by the reduction of (99m)TcO(4)(-) into [(99m)TcN](2+) with stannous chloride in the presence of succinic dihydrazide and propylenediamine tetraacetic acid, followed by the addition of the sodium salt of N-isopentyl dithiocarbamate. The radiochemical purity of the complex was over 90% as measured by thin layer chromatography. In vitro studies showed that the complex possessed good stability under physiological conditions. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed the complex was neutral. Biodistribution in mice showed that the complex accumulated in brain with high uptake and good retention. The brain uptake (ID%/g) was 2.22, 2.06 and 2.45 and the brain/blood ratio was 1.01, 2.34 and 3.22 at 5, 30 and 60 min post-injection, respectively. These results for the complex suggested that it could be a potential brain perfusion imaging agent.     

心肌显像剂~(99m)TcN(NOEt)_2的临床前药理研究

对心肌显像剂９９ｍＴｃＮ（ＮＯＥｔ）２（ＮＯＥｔ：Ｎ乙氧基，Ｎ乙基氨荒酸钠盐）进行了临床前药理研究，主要包括兔血药清除动力学，大鼠体内分布，狗显像及毒性等。制备的９９ｍＴｃＮ（ＮＯＥｔ）２放化纯度大于９０％，室温放置６小时稳定。分布半衰期＝２５３分钟，消除半衰期＝３３０分钟，清除率＝３７８ｍｌ／ｈ。药物能很快被大鼠心肌摄取并保留，５、３０、６０和９０分钟时分别为４６９、４２０、３９５和３４３％ＩＤ／ｇ，６０分钟时心／肺比值为１１６。狗显像显示９９ｍＴｃＮ（ＮＯＥｔ）２从肺中清除比心肌快，１０、３０和６０分钟时的心／肺比值分别为１６９、２４０和２５５，３０分钟心肌显像清晰，９０分钟全身显像显示心肌摄取为２８２％ＩＤ，但肝脏摄取高达３０１３％ＩＤ。小鼠对药物的耐受量为人的６１４倍。研究表明，９９ｍＴｃＮ（ＮＯＥｔ）２具有临床研究价值。     

心肌灌注显像剂^99mTc—tetrofosmin的制备和实验研究

进行新型心肌灌注显像剂ｔｅｔｒｏｆｏｓｍｉｎ的化学合成、药盒制备、９９ｍＴｃ标记、质量控制以及药理研究。方法：有机合成显像剂配体ｔｅｔｒｏｆｏｓｍｉｎ，正交实验确定９９ｍＴｃ标记药盒组分及配比，测定药盒及９９ｍＴｃｔｅｔｒｏｆｏｓｍｉｎ的理化性质，并通过药理实验确定其生物性能和安全性。Ｔｅｔｒｏｆｏｓｍｉｎ合成产物经１ＨＮＭＲ证实并制成药盒；该药盒经与９９ｍＴｃＯ－４混合，室温放置２０分钟后，可得到放化纯度大于９０％的９９ｍＴｃｔｅｔｒｏｆｏｍｉｎ，标记方法简便，标记产物稳定性好；小鼠分布实验显示较高的心／肝、心／肺比（６０分钟分别为４２６±２００和８９７±３２６）及较快的血清除速率（注射后２分钟全血百分注射剂量小于５％）；药盒各项技术指标符合药典体内诊断试剂的规定。结果表明，所研制的９９ｍＴｃｔｅｔｒｏｆｏｓｍｉｎ及其药盒达到临床试用质量。     

Search for polynuclear pentavalent technetium complex of dimercaptosuccinic acid [Tc(V)-DMS] tumour localization mechanism

To search for the tumour localization mechanism of Tc(V)-DMS, a polynuclear pentavalent technetium complex of dimercaptosuccinic acid [Tc(V)-DMS], the development of medullary thyroid carcinoma (MTC) bearing mouse model was considered. Subcutaneously transplanted tumour was allowed to grow for 2, 4 and 6 weeks, and the influence of the tumour stage on the biodistribution of Tc(V)-DMS was screened. High radioactivity uptake in the tumour tissue was observed, and this accumulation showed a direct correlation with tumour growth and calcitonin secretion, the MTC marker detectable in the blood serum. The gathered data implicated some calcitonin-related factors as the mediator in the Tc(V)-DMS localization; participation of a phosphate-like oxoanion, TcO₄ ^3–, is strongly suggested not only by the high radioactivity accumulation in the calcitonin-producing tumour but also by the accumulation in the bones of this model animal.Offprint requests to: A. Yokoyama     

Studies of chemical and biological properties of 99mTc-DMS (dimercaptosuccinic acid)--renal imaging agent.

Studies of the chemistry of preparation of tin chelate 2.3-dimercaptosuccinic acid (DMS) complexed with 99mTc with respect to its biological properties have been made. We have varied molar ratio of reactants (DMS:Sn/II/), concentration of Sn-DMS chelate and pH of 99mTc-DMS injection solution and examined their influence on biodistribution. Biodynamics of labeled solution at time intervals of from 0.5 to 4 h have also been measured. Animal experiments were carried out on mice and rats. Radiochemical purity was checked by paper chromatography, thin-layer chromatography, and gel-filtration through Bio-Gel P-2. A sterile, pyrogen-free lyophilized "kit" for labeling, stable for 6 months, was made on the basis of achieved results. The results of its clinical application are also reported.     

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.