Technetium-99m ethylene dicysteine: a new renal tubular function agent

Technetium-99m ethylene dicysteine (EC), a metabolite of ethylene cysteine dimer (ECD), is a new technetium-labelled renal tubular function tracer introduced as an alternative to ortho-iodohippurate (OIH) and with imaging qualities similar to 99mTc-mercaptoacetyltriglycine (MAG3). The elimination of ^99mTc-EC is principally via active tubular transport. It is available in lyophilised kit form which can be easily prepared at room temperature, and the compound remains stable for at least 8 h. Both in normal individuals and in patients, plasma clearance of ^99mTc-EC has been reported to be around 0.75 of OIH clearance. Thus there is a very strict correlation between ^99mTc-EC and OIH clearance, and several algorithms are available to estimate OIH clearance from ^99mTc-EC clearance. The renal extraction ratio of ^99mTc-EC is 0.70. The distribution volume of ^99mTc-EC is twice that of ^99mTc-MAG3 (20% of body weight) and slightly higher than that of OIH. The plasma protein-bound fraction of ^99mTc-EC (30%) is significantly lower than that of ^99mTc-MAG3 and OIH. The same applies to red blood cell binding of ^99mTc-EC (5.7%). There is negligible uptake in the liver and intestines. Within 1 h 70% of ^99mTc-EC is excreted in the urine. ^99mTc-EC provides the same scintigraphic information as ^99mTc-MAG3. The lower liver activity makes ^99mTc-EC particularly attractive in patients with renal failure. The ^99mTc-EC clearance can be accurately estimated from a single plasma sample obtained at 54 min after injection. In conclusion, ^99mTc-EC is a suitable renal imaging agent and for some applications is even more attractive than OIH: it provides an index of tubular function and yields high-quality images. The labelling procedure is easy, radiochemical purity is high and the complex is stable for a long time. The extent to which ^99mTc-EC is adopted for clinical use will ultimately depend upon its cost and availability.     

Technetium-99m (99mTc) mercaptoacetyltriglycine: update on the new 99mTc renal tubular function agent.

Technetium-99m (99mTc) mercaptoacetyltriglycine (MAG3) is a new renal radiopharmaceutical that was recently introduced as a 99mTc-labeled replacement for iodine-131 (131I) o-iodohippurate (OIH). Since its introduction, a wide variety of in vitro and in vivo studies have been performed to characterize the high-performance liquid chromatography (HPLC)-purified complex and kit formulations. [99mTc]MAG3 has a slower plasma clearance, a higher plasma protein binding, less red blood cell (RBC) penetration, a lower extraction ratio, and a smaller volume of distribution than OIH. Because of the slower plasma clearance, [99mTc] MAG3 cannot be used as a direct measurement of effective renal plasma flow. Simplified methods have been developed to calculate [99mTc]MAG3 clearances, as well as regression equations to convert these clearances to an equivalent OIH value. The image quality of [99mTc]MAG3 is superior to [131I]OIH; the renogram curves and the fraction of the dose of the two agents that appears in the urine are almost identical, even though the plasma clearance of [99mTc]MAG3 is only 50% to 65% that of OIH. [99mTc]MAG3 compares favorably with OIH in patients with a wide range of clinical problems. The radiation dose to a patient with normal renal function using standard imaging doses is higher for [99mTc]MAG3 than for [131I]OIH, but in patients with impaired renal function, the radiation dose from [131I]OIH is much higher than [99mTc]MAG3. [99mTc]MAG3 also provides superior image quality compared with [99mTc]diethylenetriaminepentaacetic acid (DTPA) in patients with impaired renal function, but it is important to note that [99mTc]MAG3 cannot be used to measure the glomerular filtration rate (GFR). [99mTc]MAG3 is the most promising 99mTc tubular function agent to date, and it has replaced OIH and [99mTc]DPTA in a number of institutions. However, there are physiologic differences between these three agents and, therefore, they should not be expected to behave identically in all clinical conditions.     

Technetium-99m dextran: a promising new protein-losing enteropathy imaging agent

The purpose of this study was to evaluate technetium-99m dextran (^99mTc-Dx; molecular weight 81000) as a prospective protein-losing enteropathy (PLE) imaging agent. Twenty-two patients with diseases commonly associated with PLE and 12 healthy control subjects underwent intravenous^99mTc-Dx scintigraphy. All of the 22 test patients showed significant radiotracer accumulation in the intestines within 3–4 h post injection. The focal, regional or generalised nature of the enteropathy and involvement of the large or small intestine could be identified in most cases. Four of the 12 apparently healthy subjects also showed minimal accumulation in the abdominal area occurring late in the study period. This could have been physiological, related to food habits or due to unsuspected intestinal worms. We attribute the high sensitivity of^99mTc-Dx to its relatively fast blood (background) clearance. The radiotracer may have several other advantages over^99mTc-labelled human serum albumin in imaging PLE.     

Technetium-99m labelled bran: a new agent for measuring gastric emptying

Bran was labelled with 99mTc-pertechnetate, ingested as part of a normal meal and used to measure gastric emptying in 15 normal subjects and in 15 patients with ulcerative colitis. There was no significant difference between the gastric emptying curves of the normal subjects and the patients, suggesting that rapid gastric emptying does not contribute to diarrhoea in ulcerative colitis.     

Technetium-99m-labeled p-aminohippuric acid analog: a new renal agent: concise communication

A renal agent labeled with Tc-99m and quantitatively secreted by the tubules has been sought for many years. To meet this need, a PAH analog (PAHIDA), has been synthesized by the coupling of p-aminohippuric acid with nitrilotriacetic acid anhydride, using Sn(II) reduction. This yields a stable complex with Tc-99m at a pH of 5.8. The purity and stability of the Tc-99m complex have been established by ITLC and high performance liquid chromatography (HPLC). Urinary excretions of the Tc-99m PAHIDA and I-131 hippurate, determined in mice and rats at different time intervals, are similar. The new compound is clearly excreted but its total clearance is lower than that of hippurate as a result of high protein binding. Rat urine analysis by ITLC and HPLC suggests that the agent excreted is similar to the complex administered to the animals. The Tc-99m-labeled agent is rapidly excreted in urine with no significant extrarenal pathway, thus providing excellent renal scintigrams in a rabbit model. The Tc-99m PAHIDA contains the R-CO-NH-CH2-COOH grouping, analogous to that in hippurate, and consequently may provide the substrate specificity for renal excretion of this new class of agents labeled with technetium-99m.     

Technetium-99m DTPA dimethyl ester: a renal function imaging agent. Comparative studies in animals with technetium-99m mercaptoacetyl triglycine and 131I-ortho-iodohippurate

The dimethyl ester of diethylene triamine penta-acetic acid (DMDTPA) (I) can be easily and efficiently labelled with 99mTc. This method can be readily adapted for kit formulations to produce a highly stable and very pure chelate, as shown by paper electrophoresis and reverse-phase high performance liquid chromatography experiments. In mice, this chelate was excreted unchanged in the urine, and the amount of renal excretion was much higher than that of 99mTc-DTPA and comparable with that of 99mTc-mercaptoacetyl triglycine (99mTc-MAG(3)) at two different time points. The renal excretion of co-injected 131I-ortho-iodohippurate (131I-OIH), however, was significantly greater than that of the 99mTc chelates. The renal clearance values of 99mTc-DMDTPA and 99mTc-MAG(3) were also similar and exceeded the corresponding value for 99mTc-DTPA, but were only half that of the 131I-OIH value in the rat. The renograms for 99mTc-DMDTPA and 99mTc-MAG(3) showed overall similarity in a dog model. The diethyl ester (III) and monoethyl ester (II) of DTPA, after labelling with 99mTc, produced the same chelate, as shown by analytical results and biological data, indicating that one of the ester groups in the DTPA diester is dealkylated during the chelation procedure. To confirm this, two more ligands, diethylene triamine 1,4,7,7-tetra-acetic acid (IV) and diethylene triamine 1,4,7-triacetic acid (V), were synthesized, resembling DTPA monoalkyl ester (II) and dialkyl ester (I, III), respectively, in the arrangement of the donor atoms. Ligand IV but not ligand V, on 99mTc chelation, can generate the specific pharmacophore for renal tubular transport that is also present in the ester chelates 99mTc-I, 99mTc-II and 99mTc-III, as shown by their decreased renal excretion in mice pretreated with a renal tubular transport inhibitor such as probenecid.     

Technetium-99m APD compared with technetium-99m MDP as a bone scanning agent

We have investigated the possibilities of technetium-99m-(-3-aminohydroxypropylidene)-1-1-bisphosphon ate ([99mTc]APD) as a bone scanning agent in 14 normal subjects and 28 patients. Similar studies in the same normal subjects and patients were carried out with 99mTc-methylene-bisphosphonate ([99mTc]MDP). The compounds were labeled with 99mTc by means of an electrolytical method; the free pertechnetate content was always under 1%. The [99mTc]APD T1/2 of the third component of the disappearance plasma curve in six normal subjects was 152 +/- 46 min (mean +/- s.d.), while the 24-hr whole-body retention (WBR) was 17.6% +/- 4.6. The [99mTc]MDP value of the 24-hr WBR was 28.6% +/- 3.9 (p less than 0.001). The bone/soft-tissue ratio (B/ST) was investigated in eight control subjects on the eleventh thoracic and the fourth lumbar vertebrae. The B/ST ratios were similar for both APD and MDP studies. In 28 patients with suspected bone metastasis or primary bone disease, bone scintigraphy was carried out; both compounds showed similar findings and the same number of positive results. In five of these patients, the lesion/normal bone ratio was determined with values of 4.6 +/- 2.0 in APD studies and 4.8 +/- 2.3 with MDP. APD was also used in 126 patients; no adverse reactions were observed. The APD dose used i.v. for bone scanning was 200-fold less than those employed by mouth per day, for the treatment of bone disease for long periods. In our experience, APD appears to be an adequate agent for bone scintigraphy.     

Evaluation of renal function in low-dose cyclosporine-treated patients using technetium-99m diaminocyclohexane: a cationic tubular excretion agent

Technetium-99m diaminocyclohexane (DACH) is a new tubular agent excreted via a cationic transport mechanism, like cyclosporine-A (CsA). It is expected that ^99mTc-DACH will permit effective assessment of tubular function in CsA-treated patients. To establish the pharmacokinetic characteristics of ^99mTc-DACH and to ascertain whether this new agent is useful in CsA-treated patients, 11 healthy volunteers and 15 CsA-treated patients underwent renal imaging and clearance studies using ^99mTc-DACH and chromium-51 ethylene diamine tetra-acetic acid (EDTA). ^99mTc-DACH yielded satisfactory dynamic renal images in all participants. The mean plasma clearance of ^99mTc-DACH was significantly greater than that of ⁵¹Cr-EDTA in volunteers (109.4±19.7 ml/min versus 86.6±13.7 ml/min, P<0.05). However, the urinary excretion of ^99mTc-DACH at 90 min was significantly lower than that of ⁵¹Cr-EDTA (46.1%±9.3% versus 53.1%±8.6%, P<0.05), most probably due to its partial parenchymal retention. The elimination half-life of ^99mTc-DACH was significantly increased in CsA-treated patients in comparison to volunteers, and consequently the plasma clearance values were significantly suppressed in these patients, in contrast to ⁵¹Cr-EDTA and endogenous creatinine clearance values. In conclusion, our findings indicate that ^99mTc-DACH, as a sensitive marker of cationic tubular function, could be used to monitor renal haemodynamics in patients receiving CsA treatment. Received 19 June and in revised form 28 July 1998     

Technetium-99m glucoheptonate as a scanning agent in hepatocellular carcinoma

Technetium-99m glucoheptonate (Tc-99m GH) is concentrated in pulmonary and cerebral tumors. The purpose of this study was to assess the uptake of this radionuclide by hepatocellular carcinoma. Its concentration by the primary tumor was compared with that in the non-neoplastic hepatic tissue in 31 patients who showed obvious defects on a colloid scan, and its uptake by pulmonary metastases was examined in six patients with x-ray evidence of this complication. In two patients, the uptake by the tumor was greater than, in six it was equal to, and in ten it was less than that in the non-neoplastic hepatic tissue. In the remaining 13 patients, there was no concentration at all in the tumor. In none of the six patients with multiple pulmonary metastases could uptake of Tc-99m GH by the metastases be demonstrated. It is concluded that Tc-99m GH is of limited value in the diagnosis of primary or metastatic hepatocellular carcinoma.     

Technetium-99m complex ofN-(2-pyridylmethyl)iminodiacetic acid as a new renal radiopharmaceutical

A tetradentate chelating agent constituting of an iminodiacetic acid group and a nitrogen atom of pyridine, N-(2-pyridylmethyl)iminodiacetic acid (PMIDA), was coordinated with 99mTc and evaluated as a renal functional agent. The complex of PMIDA with 99mTc was prepared by using a stannous chloride solution as a reducing agent. The chelating efficiency was analyzed by thin layer chromatography and electrophoresis. Chelation with 99mTc resulted in a single radiochemical product. Biological studies were performed in mice and rats. 99mTc-PMIDA was removed from the circulation solely by the kidneys. Clearance of 99mTc-PMIDA from the blood and the kidneys was as rapid as that of 99mTc-diethylenetriaminepentaacetic acid. The rate of blood clearance was unaffected by the administration of probenecid (a test for tubular secretion by the weak-acid mechanism), so that the glomerular filtration rate could be estimated by measuring its clearance from the blood. The results in animals with myohemoglobinuric acute renal failure suggested that 99mTc-PMIDA might be a useful renal function radiopharmaceutical.     

Technetium-99m DTPA renal flow studies in Goldblatt hypertension

Computer-assisted dynamic renal studies were performed on a group of 14 mongrel dogs before and after the induction of unilateral renal artery stenosis. Ninety-second technetium-99m diethylenetriaminepentaacetic acid ( [99mTc]DTPA), 15-min [99mTc]DTPA, and 30-min iodine-131 orthoiodohippurate ( [131I]hippuran) time-activity curves were analyzed and correlated with reduction of renal blood flow as measured by electromagnetic flow probe and PAH clearance techniques. Parameters of the 90-sec [99mTc]DTPA curves found to be significantly different for the same kidney before and after stenosis were: upslope, curve width at 75% maximum, maximum activity value, and differential (stenotic/contralateral) maximum activity ratio. For blood flow reductions greater than 33%, the [99mTc]DTPA studies were judged diagnostic of unilateral renal artery stenosis in all cases, whereas the [131I]hippuran time-activity curves were indicative of stenosis in only six of ten studies. Thus, in this model we find the computer-assisted 90-sec [99mTc]DTPA renal flow study to be superior to conventional [131I]hippuran renography in the diagnosis of moderate-to-severe unilateral renal artery stenosis.     

Technetium-99m teboroxime scintigraphy

In order to evaluate the clinical value of a new myocardial perfusion tracer, a series of 30 patients (25 male, 5 female, mean age 56 years) referred for thallium 201 stress/redistribution scintigraphy has been studied using stress/rest (n = 7) or rest/stress (n = 23) protocols with technetium 99m teboroxime (Cardiotec SQUIBB). In all cases coronary artery disease was known or highly probable, with a history of myocardial infarction in 18 cases. Medical treatment was not discontinued at the time of stress testing, and coronary angiography was available in 27 patients. Exercise tests for both tracers were carried out on a bicycle ergometer during the same day, and the levels of exercise achieved for the ²⁰¹Tl study were very similar to those achieved for 99^mTc-teboroxime. Studies performed in three planar projections were evaluated using a model with four territories septal and anterior assumed to correspond to the left anterior descending artery, lateral and lateroposterior (left circonflex), inferior and posterior (right coronary artery) and apex. Classification of results was normal, ischaemic, infarcted and infarcted with ischaemia. On comparison with the ²⁰¹Tl results, agreement was found in 86% (37/43) of normal regions and in 82% (63/77) of abnormal regions. Relative to documented coronary artery lesions (27 patients), sensitivity and specificity of ²⁰¹Tl and ^99mTc-teboroxime for exact correspondence between arteries and territories were respectively: ²⁰¹Tl: sensitivity 64%, specificity 60%; ^99mTc-teboroxime: sensitivity 62%, specificity 77%. These results, obtained in a given clinical context, indicate the ability of Cardiotec to evaluate myocardial perfusion with a significant saving in time, since the complete study duration (stress and rest) was: ²⁰¹Tl, 4 h 35 min±21 min; ^99mTc-teboroxime, 1 h 52 min ±29 min. Nevertheless, the high liver uptake was responsible for 68% of non-evauble inferior segments and the limited acquisition time makes the applicability of SPET questionable.