Comparison of technetium-99m MAG3 with iodine-131 hippuran by a simultaneous dual channel technique

Technetium-99m MAG3, a technetium-labeled analog of hippuran, was compared with [131I] hippuran using a simultaneous dual isotope study in 20 patients. The plasma clearance for MAG3 was lower than that of hippuran, but its plasma concentration was higher, resulting in similar rates of excretion and similar renal time-activity curves. Apart from better statistics with the technetium-labeled agent, there were no clinically significant differences in this group of patients.     

Comparison of technetium-99m MAG3 kit with HPLC-purified technetium-99m MAG3 and OIH in rats

Technetium-99m (99mTc) mercaptoacetylglycylglycylyglycine (MAG3) in high (greater than or equal to 95%) radiochemical purity is prepared from lyophilized kits containing benzoylMAG3, sodium tartrate, lactose, and stannous chloride by adding sodium [99mTC]pertechnetate and heating the contents briefly. Constant-infusion renal whole-blood clearance obtained with [99mTc] MAG3 kits was compared with that obtained with high performance liquid chromatography (HPLC) pure [99mTc]MAG3 and with co-infused iodine-131 (131I) iodohippurate (OIH) in anesthetized rats. Average renal whole-blood clearance of [99mTc]MAG3 from kits was 3.9 +/- 0.4 ml/min/100 g body weight (mean +/- s.e.m. n = 5) and that for HPLC-pure [99mTc]MAG3 was 4.6 +/- 0.3 (n = 3). Renal whole-blood clearance ratios for [99mTc]MAG3 to co-infused iodine-131 (131I) OIH were greater than unity for both kit formulation (1.7 +/- 0.1) and HPLC-pure [99mTc]MAG3 (1.9 +/- 0.2). Differences in these two measures were not significant. Plasma binding (determined from blood drawn at the end of the infusion) of [99mTc]MAG3 prepared from both kits (75 +/- 2%, n = 4) and HPLC-separation (76 +/- 4%) were greater than that of [131I]OIH in corresponding plasma samples (31 +/- 1% and 32 +/- 2%) respectively). Renograms performed in anesthetized rats revealed no statistically significant differences between kit-prepared [99mTc]MAG3 and [131I]OIH in terms of time-to-peak renal activity (5.0 +/- 1.7 min, n = 6; and 2.2 +/- 0.2 min, n = 3, mean +/- s.e.m. for [99mTc]MAG3 and [131I]OIH, respectively), in terms of time to fall to half-maximal activity (15.3 +/- 2.4 min and 9.6 +/- 2.1 min, respectively), or in terms of fraction of peak radioactivity in right kidney (0.53 +/- 0.01 for both substances). To assess possible interference from hepatobiliary uptake and excretion in renal failure, radioactivity in liver regions of interest was followed by gamma camera scintigraphy for 30 min after intravenous injection of [131I]OIH and kit and HPLC-purified [99mTc]MAG3 in anesthetized rats rendered anephric by ligating renal peduncles. Liver activity was 25% of total for both preparations of [99mTc]MAG3 and was 22% of total for [131I]OIH. There were no significant differences among the substances.     

Quantitation of renal function with technetium-99m MAG3

The technetium-labeled hippuran analog [99mTc]MAG3 was compared with [131I]hippuran in 50 patients using a quantitative renal function protocol that includes: (a) estimation of effective renal plasma flow by a single-injection, single-sample plasma clearance method, (b) determination of relative function of right and left kidney from the initial count rate over each kidney, and (c) comparison of recovered urine activity with plasma disappearance. This protocol is suitable for routine clinical use, and, in fact, has been used heavily at our clinic for a number of years. By slight modification of the formulas, the results obtained with [99mTc]MAG3 agreed well with those using [131I]hippuran. We conclude that [99mTc]MAG3 can be substituted for [131I]hippuran in the quantitative protocol, with the better image quality and lower radiation dose (in abnormals) of a technetium-labeled agent.     

A comparative evaluation of iodine-131 OIH and technetium-99m MAG3 in the study of renal function

A new renal imaging agent, 99mTc mercaptoacetyltriglycine (MAG3), has been recently proposed in the nuclear medicine evaluation of renal function. Just like 131 orthoiodohippurate (OIH), 99mTc MAG3 is removed mainly by the renal tubules. An heterogeneous group of 39 patients underwent a radioisotopic study with the simultaneous injection of OIH (131I) and 99mTc MAG3. Image quality was found to be better with 99mTc MAG3 than with OIH (131I), because the former always allowed renal regions of interest (ROI) to be clearly demonstrated, even in case of severe renal impairment. A quantitative analysis was also carried out: effective renal plasma flow (ERPF) values were compared with renographic peak times evaluated by using both radiotracers. Our results demonstrate a firm correlation to exist between the informative content yielded by 99mTc MAG3 and by OIH (131I). Absolute ERPF value was higher with MAG3, but the correlation index (r = 0.98) allowed a simple correction factor to be introduced. In conclusion, MAG3 appears to be a good alternative to OIH.     

Dynamic SPECT evaluation of renal plasma flow using technetium-99m MAG3 in kidney transplant patients.

OBJECTIVE: The purpose of this study was to evaluate Patlak's graphic analysis method to determine renal plasma flow (RPF) in kidney transplants. METHODS: Dynamic SPECT was performed with 99mTc MAG3 in 12 patients. RPF was determined by both Patlak's graphic analysis method and Russell's method. Ventral, central and dorsal tomographic images of the transplanted kidney were reconstructed to estimate intrarenal distribution of renal plasma flow. RESULTS: The renal influx constant (Ku) calculated by Patlak's graphic analysis method was reproducible and correlated with both serum creatinine (r = -0.88, P < 0.001) and blood urea nitorogen levels (r = -0.82, P < 0.002). However, a significant difference was noted between the RPF values derived from Patlak's graphic analysis method and Russell's method. Ku was corrected by a factor calculated from raw and reconstructed data, and the resulting values were in fair agreement with those determined by Russell's method. CONCLUSION: These methods are useful in evaluating the function of transplanted kidneys.     

Comparison of iodine-131 OIH and technetium-99m MAG3 renal imaging in volunteers

Animal studies have suggested that the nonisomeric N3S triamide mercaptide ligand, 99mTc mercaptoacetyltriglycine (MAG3), may provide a satisfactory 99mTc-labeled replacement for 131I hippurate (OIH). Sequential 30-min [99mTc]MAG3 (5-10 mCi) and [131I]OIH (300 microCi) imaging studies were performed in ten normal volunteers in order to compare the image quality, renal excretion, blood clearance, and time to peak height of the renogram curve. In addition, [99mTc] MAG3 (5 mCi) and [131I]OIH (150 microCi) were administered simultaneously in eight volunteers for comparison of 180-min blood and plasma clearances and urine excretion. In the sequential imaging studies, the blood clearance of [99mTc]MAG3 was more rapid than [131I]OIH with a mean clearance of 1.30 l/min compared with 0.88 l/min for [131I]OIH (p less than 0.05). Seventy-three percent of the injected dose of the MAG3 was excreted by 30 min compared with 66.8% for [131I]OIH. Whole kidney and cortical renogram curves showed no significant difference in the time to peak height for MAG3 and [131I]OIH. In all subjects, the quality of the [99mTc]MAG3 images were clearly superior to [131I]OIH. Following simultaneous injection, blood and plasma clearances for [131I]OIH were more rapid than MAG3 when determined for multiple time intervals from 0-30 to 0-180 min (p less than or equal to 0.05). The 0-30-min clearances of MAG3 and [131I]OIH were only slightly greater than the 0-180-min clearances and can be used to obtain valid comparisons of the two agents. As in the sequential study, 30-min urine excretion was greater for MAG3 than [131I]OIH (73.1 compared with 69.6%) but the difference was not statistically significant. Although the differences in the MAG3 clearances following sequential and simultaneous administration are not satisfactorily explained, the fact that both clearances were rapid, the MAG3 and OIH renogram curves were quite similar, and 30-min urine excretions of MAG3 and OIH were essentially identical suggests that MAG3 may become a 99mTc replacement for [13I]OIH and further clinical evaluation is warranted.     

Abnormal captopril renogram with a technetium-99m-labeled hippuran analog

A case of renovascular hypertension is presented in which the [131I]hippuran renogram was initially normal, but became strikingly abnormal upon administration of the angiotensin converting enzyme (ACE) inhibitor captopril. The patient presented with fibromuscular dysplasia of the renal arteries, which was shown by hippuran renography to be functionally significant on the right side. She became normotensive after angioplasty of the right renal artery. Hypertension recurred a year later, at which time the renogram was normal without captopril, but showed functionally significant left renal artery stenosis with captopril challenge. Both the conventional agent, [131I]hippuran, and an experimental new 99mTc-labeled hippuran analog, [99mTc]MAG3, were used. Angiography confirmed progression of disease on the left side, which was successfully treated by angioplasty. Functionally significant unilateral renal artery stenosis was thus demonstrated first on the right side and then, 1 yr later, on the left side, using hippuran and [99mTc]MAG3. Anatomic progression of disease was documented by angiography.     

Synthesis and biological evaluation of the four isomers of technetium-99m labeled ethylenecysteamine cysteine ((99m)Tc-ECC), the mono-acid derivative of (99m)tc-L,L-ethylenedicysteine

A few years ago (99m)Tc-ethylenedicysteine ((99m)Tc-L,L-EC) had been proposed as an interesting substitute for technetium-99m labeled mercaptoacetyltriglycine (MAG3) as renal function tracer agent. It possesses in its structure two carboxylate functions and is in this respect different from other renal tracers such as (99m)Tc-N, N'-bis-(mercaptoacetyl)-2,3-diaminopropionate ((99m)Tc-CO(2)DADS), (99m)Tc-MAG3, and Hippuran, which have only one carboxylic group. To study whether both carboxylic acid groups of (99m)Tc-L,L-EC contribute to the efficient renal handling of this compound we synthesized and biologically evaluated the technetium-99m labeled isomers of L- and D-ethylenecysteamine cysteine (ECC), the mono-acid derivative of (99m)Tc-L,L-EC. Labeling of L-ECC or D-ECC with (99m)Tc using a direct or exchange labeling method yields for each of them two diastereomeric (99m)Tc complexes (A and B, in the order of elution during reversed phase high performance liquid chromatography) in relative amounts depending on the pH during labeling. In mice, all four isomers of (99m)Tc-ECC (LA, LB, DA, and DB) are cleared rapidly from the blood, mainly by the renal system. The isomers LB and DB show the most efficient renal handling, but none of the mono-acid derivatives has a urinary excretion rate as high as that of (99m)Tc-L,L-EC. The renal handling of the isomers of (99m)Tc-ECC is partly due to tubular secretion because the urinary excretion of these compounds is significantly lower in mice pretreated with probenecid. In the baboon, isomers DA and DB show a plasma clearance comparable to that of (99m)Tc-L,L-EC. The plasma clearance of isomers LA and LB is lower but still comparable to or higher than that of (99m)Tc-MAG3. In a human volunteer, isomer DB shows a plasma clearance rate only slightly lower than that of (99m)Tc-L,L-EC. Thus, it appears that the presence of one carboxylate in (99m)Tc-EC-like compounds can be sufficient for efficient renal handling. However, it is also evident that the configuration at the chiral carbon atom and the orientation of the oxotechnetium core determine in a significant way the biological characteristics.     

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.     

Synthesis,radiochemistry and biological evaluation of a new somatostatin analogue (SDZ 219–387) labelled with technetium-99m

A new derivative of octreotide SDZ 219-387 [PnAO-(D)Phe¹-octreotide] was synthesized, which binds specifically and with high affinity to somatostatin receptors in vitro (pK= 9.79±0.16). This new somatostatin analogue chelates technetium-99m under mild labelling conditions in good yields. The resulting [^99mTc]SDZ 219–387 was stable up to 6 h after labelling and could be isolated in a pure radiochemical and chemical form by high-performance liquid chromatographic purification. The intravenous administration of purified [^99mTc]SDZ 219–387 revealed that the radioligand was rapidly cleared from circulation, and tumour uptake of 0.38% ID/g was observed at 1.5 h post injection. [^99mTc]SDZ 219–387 specifically interacted with somatostatin binding sites on the tumour. However, the radioligand is highly lipophilic and excreted mainly through the hepatobiliary system. As a consequence, [^99mTc]SDZ 219–387 exhibits increased background activity and therefore is not appropriate for the in vivo visualization of somatostatin receptor-positive tumours and/or their metastases in the abdomen. Correspondence to: T. Maina     

Adsorption of technetium-99m tetrofosmin and technetium-99m furifosmin on plastic syringes

Some groups have reported that adsorption of radiopharmaceuticals on disposable plastic syringes can reach levels of almost 50%. This high loss of radioactivity stimulated us to carry out similar studies. Our measurements were done in combination with patient studies. Therefore, we used 2-ml syringes, all of the same brand. The radioactivity in the syringe was measured immediately before and after injection. a total of 500–600 MBq technetium-99m labelled tetrofosmin or technetium-99m furifosmin was administered to 48 patients using four different injection techniques (n = 6 for each technique with each tracer): with needles, 1 min blood incubation at 22°C, 10 or 30 min after preparation of the tracer; with butterflies, 1 min blood incubation at 22°C, 10 or 30 min after preparation of the tracer. Neither in syringes nor in needles or butterflies did more than 7% of the initial radioactivity remain. The entire residual activity in syringe plus needle or syringe plus butterfly together never exceeded the 9% limit. Furthermore, in a pilot study we measured the remaining radioactivity in the vial; here, too, we found no more than 14% of total radioactivity. These findings indicate that total retention of radioactivity during elution and application of ^99mTc-tetrofosmin and ^99mTc-furifosmin with material used in our setting does not approach relevant amounts. Received 6 May and in revised form 19 May 1998     

Parathyroid scintigraphy: comparison of technetium-99m methoxyisobutylisonitrile and technetium-99m tetrofosmin studies

We report the preliminary results of a prospective study demonstrating tetrofosmin uptake in surgically and histologically proven parathyroid adenomas. In ten patients with primary chronic hyperparathyroidism, parathyroid imaging was performed using (1) technetium-99m methoxyisobutylisonitrile (MIBI) and (2)^99mTc-1,2-bis(bis(2-ethoxyethyl)phosphino)ethane (tetrofosmin) within a time interval of 3–5 days. Both tracers correctly identified the parathyroid adenomas by focal prolonged tracer retention. On visual inspection image contrast was generally higher with MIBI than with tetrofosmin in all the patients studied. Tetrofosmin showed a slower elimination from the parathyroid adenomas than MIBI in six of the ten cases. Our preliminary results show that tetrofosmin, like MIBI, as a feasible, sensitive tracer for parathyroid scintigraphy. For routine use, the rapid kit preparation without heating and the lower radiation dose to the patient make tetrofosmin an alternative tracer for parathyroid scintigraphy. Further evaluation is needed to determine which of the two tracers is the more sensitive for the detection of parathyroid adenomas, and which tracer properties better reflect the degree of endocrine activity.[/p]     

Comparative scanning of thyroid nodules with technetium-99m pertechnetate and technetium-99m methoxyisobutylisonitrile

Thyroid imaging was performed using technetium-99m methoxyisobutylisonitrile and technetium-99m pertechnetate in 58 patients. The ^99mTc-pertechnetate scans showed a total of 77 nodules: 60 cold, 13 hot and 4 of normal activity. There was no ^99mTc-MIBI accumulation in 46.4% of ^99mTc-pertechnetate cold nodules; 27 (45%) of these nodules showed ^99mTc-MIBI uptake with the same intensity as the surrounding normal tissue, and five (8.6%) became hot with ^99mTc-MIBI. Of the ^99mTc-pertechnetate hot nodules 11 (84.6%) could not be differentiated from the normal extranodular tissue on the ^99mTc-MIBI scan. The histopathology of 34 surgically removed nodules proved that increased, normal or decreased ^99mTc-MIBI accumulation is not specific for thyroid malignancy and that the ^99mTc-MIBI uptake depends mainly on the viability of thyroid tissue.Correspondence to: I. Földes     

Technetium-99m mercaptoalbumin as a potential substitute for technetium-99m labelled red blood cells

Technetium-99m labelled red blood cells (^99mTc-RBCs) are far superior to ^99mTc-labelled human serum albumin (^99mTc-HSA) for radionuclide ventriculography, but their labelling is more complex, time consuming and risk bearing (in vitro labelling) or suffers from interference by some medications (in vivo labelling). We have now modified HSA by the introduction of mercapto groups with the purpose of preparing stable and practical ^99mTc-mercaptoalbumin with long retention in the vascular system, that could replace ^99mTc-RBCs. HSA was incubated with N-succinimidyl S-acetylthioacetate (SATA) or N-succinimidyl 2,3-di(S-acetylthio) propionate (SATP) to introduce a chain containing one or two protected sulfhydryl groups on some of the lysine amino groups. After purification by size-exclusion chromatography (SEC), the mercapto groups were deprotected by incubation at alkaline pH or by treatment with hydroxylamine. The reaction products were used with or without SEC purification for direct or exchange labelling experiments with ^99mTc at neutral pH. SEC-HPLC was used to determine labelling yields and to isolate pure ^99mTc-mercaptoalbumin. Stable ^99mTc-mercaptoalbumin complexes could be formed in 90%–95% yield after coupling albumin with SATA or SATP in all molar ratios used followed by deacetylation in one of the mentioned conditions. The most favourable results were obtained after reaction of SATA or SATP with HSA in a 25: 1 ratio and deprotection with NH₂OH. The stability of the resulting ^99mTc-mercaptoacetyl-albumin (^99mTc-MAHSA) and ^99mTc-dimercaptopropionyl-albumin (^99mTcDMP-HSA) and their retention in vivo in plasma of mice and rabbits are clearly higher than that of conventional ^99mTc-HSA preparations. ^99mTc-DMP-HSA approaches the behaviour of ¹²⁵I-HSA quite well in both animal species. A preliminary study with ^99mTc-DMP-HSA in a volunteer showed a retention in the vascular compartment almost identical to that of ^99mTc-RBCs and clearly higher than that of a common ^99mTc-HSA preparation. The results indicate that these ^99mTc-mercaptoalbumins and especially ^99mTc-DMP-HSA are very promising as a practical alternative to ^99mTc-RBCs.K.A. Verbeke is a Research Assistant for the Belgian National Fund for Scientific Research