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.     

Synthesis and biological evaluation of technetium-99m MAG3 as a hippuran replacement

A new technetium-chelating agent based on a triamide monomercaptide tetradentate set of donor groups, mercaptoacetylglycylglycylglycine (MAG3), was synthesized and evaluated. Chelation with 99mTc resulted in a single radiochemical product as expected. Studies in mice of [99mTc]MAG3 indicated excretion rates faster than omicron-iodohippurate (OIH) both in normal and in probenecid treated animals. Specificity for renal excretion was essentially complete. Clearance studies in rats resulted in 2.84 ml/min/100 g for [99mTc]MAG3, 2.17 for OIH, and 1.29 for [125I]iothalamate. Extraction efficiencies were 85% for [99mTc]MAG3, 69% for OIH and 39% for [125I]iothalamate. Probenicid depressed the clearance both of [99mTc]MAG3 and OIH at 25 and 50 mg/kg/hr, but to a greater extent with [99mTc]MAG3. The greater effect is offset, however, by the larger fraction secreted by the renal tubular cells. The animal results suggest that [99mTc]MAG3 may be a useful alternative to [131I]OIH.     

Effects of altered physiologic states on clearance and biodistribution of technetium-99m MAG3, iodine-131 OIH, and iodine-125 iothalamate

Technetium-99m mercaptoacetyltriglycine [( 99mTc]MAG3) is a new renal radiopharmaceutical with biologic properties similar to iodine-131 orthoiodohippuric acid [( 131I]OIH). MAG3 may be used as a replacement for [131I]OIH and/or [99mTc]DTPA. For this reason, we compared the effects of several potential adverse clinical conditions on the clearance and biodistribution of MAG3, OIH and a GFR marker. To simulate renal failure, five mice underwent bilateral renal pedical ligation. Twenty-four hours after surgery they were injected with MAG3 and OIH and killed 2 hr postinjection. Compared to sham operated controls, liver activity for MAG3 and OIH increased from 0.2% to 14.1% and 0.1% to 13.9%, respectively, while intestinal activity increased from 1.3% to 8.9% for MAG3 and 0.2% to 7.7% for OIH. Constant infusion studies were performed in rats to evaluate the effects of increased plasma organic acid levels, mannitol diuresis, dehydration, and acid/base imbalance on the clearance of OIH, MAG3, and [125I]iothalamate. No differences were noted between the OIH and MAG3 clearances following diuresis and dehydration and the differences involving acid/base imbalance were minimal. Dehydration depressed the clearance of [125I]iothalamate more than that of OIH or MAG3. Para-aminohippurate (PAH) infusion inhibited the clearance of MAG3 more than OIH supporting proximal tubular transport for MAG3; PAH had no effect on [125I]iothalamate. In summary HPLC purified MAG3 behaved similarly to OIH under adverse physiologic conditions and the data continue to support the use of MAG3 as a potential clinical substitute for OIH.     

Technetium-99m MAG3, a comparison with iodine-123 and iodine-131 orthoiodohippurate, in patients with renal disorders

A Phase I study in 12 patients with renal disorders compared the simultaneous clearances of 99mTc-labeled mercaptoacetyltriglycine (MAG3) and 131I-labeled orthoiodohippurate (OIH). The ratio of MAG3 to OIH clearance was 0.61 +/- 0.08 as a result of its smaller volume of distribution, ratio 0.65 +/- 0.09, for the clearance half-lives were similar, ratio 1.09 +/- 0.12. A Phase II study performed serially in 20 patients with equal doses of [99mTc]MAG3 and [123I]OIH gave images of equal quality. The relative renal functions were highly correlated (r = 0.97, p less than 0.001) and transit time analyses gave good correlations: parenchymal transit time index r = 0.81, p less than 0.05. We conclude that [99mTc]MAG3 has some advantages over [99mTc]DTPA and is a suitable replacement for [123I]hippuran in routine renal imaging, relative function, and transit time studies, but not for the accurate estimation of the renal plasma flow.     

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.     

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.     

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.     

Animal evaluation of technetium-99m triamide mercaptide complexes as potential renal imaging agents

Technetium-99m mercaptoacetylglycylglycylglycine (MAG3), a [99mTc]triamide mercaptide (N3S) compound has been synthesized in an attempt to obviate the stereochemistry problems associated with the diamide dimercaptide (N2S2) ligands. Because initial studies have been promising, the terminal glycine on the MAG3 compound has been varied to create a new series of N3S compounds. Twelve new N3S complexes were initially screened in mice and the more promising complexes, 99mTc mercaptoacetylgylcylglycyl-glycine [( 99mTc]MAG3), 99mTc mercaptoacetylgylcylglycyl-L-alanine [( 99mTc]MAG2-Ala), and both complexes of 99mTc mercaptoeacetylglycylglycyl-L-asparagine [( 99mTc]MAG2-Asn) and 99mTc mercaptoacetylglycylglycyl-L-glutamine [( 99mTc]MAG2-Gln), were further evaluated in rats utilizing constant infusion blood clearances, extraction efficiencies and protein binding assays. The renal excretion of all these complexes compared favorably with simultaneously administered [131I]OIH and [125I]iothalamate. The triamide mercaptide complexes represent a new ligand class for 99mTc, which may provide a variety of complexes for the evaluation of renal tubular function.     

Technetium-99m MAG-3 clearances after captopril in experimental renovascular hypertension

Rats with one kidney clamped (2K1C), both kidneys clamped (2K2C), unilaterally nephrectomized with remaining kidney clamped (1K1C), and normals, were studied using 99mTc mercaptoacetyltriglycine ([ 99mTc]MAG-3) and 131I orthoiodohippurate ([131I]OIH). Clearances of [99mTc]MAG-3 and [131I]OIH were performed after constricted rats became hypertensive. Clearances were repeated after i.v. Captopril. Clearances of [99mTc]MAG-3 and [131I]OIH in normals didn't change significantly after Captopril. Clearances of [99mTc]MAG-3 and [131I]OIH decreased insignificantly after Captopril in the 2K2C model. in the 2K1C group, normal kidney clearance increased ([99mTc]MAG-3 p less than 0.01 and [131I]OIH p less than 0.025) and clamped kidney clearance decreased after inhibition ([99mTc]MAG-3, p less than 0.01, [131I]OIH p less than 0.02). Clearances increased in the 1K1C group after Captopril ([99mTc]MAG-3 p less than 0.0025 and [131I]OIH, p less than 0.001). The ratio of [99mTc]MAG-3 to [131I]OIH before Captopril was 0.81 and 0.84 after Captopril. Changes in renal function after Captopril depend on the model of renovascular hypertension and possibly the dose administered. Technetium-99m MAG-3 clearance parallels [131I]orthoiodohippurate in renovascular hypertension.     

Evaluation of the renal clearance of technetium-99m PAHIDA in dogs

The renal clearance of the technetium-99m complex of para[(biscarboxylmethyl)-aminomethylcarboxyamino]hippuric acid ([99mTc]PAHIDA), has been previously studied in rodents and falls between that of [99mTc]DTPA (diethylenetriaminepentaacetic acid) and iodine-131 (131I) orthoiodohippuran (OIH). To investigate the effect of species variation, the plasma clearance of [99mTc]PAHIDA was investigated in dogs. The plasma disappearance of the renal agent approached that of [99mTc]DTPA and was significantly less than that of OIH. Despite the structural similarities of the PAHIDA ligand and aminohippurate, the [99mTc]PAHIDA complex undergoes little, if any, tubular secretion in the canine kidney.     

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.     

Estimation of technetium-99m-MAG3 plasma clearance in adults from one or two blood samples

Technetium-99m mercaptoacetyltriglycine (MAG3) clearance is strongly correlated with effective renal plasma flow and can be used directly as a measure of renal function. For these reasons, formulas were developed for estimation of [99mTc]MAG3 clearance based on one or two plasma samples. A two-exponential model provided an excellent fit for 8-point plasma clearance curves obtained from 35 patients having a wide range of renal function. The 8-point [99mTc]MAG3 clearance could be estimated from a single point at 43 min with an error of 19 ml/min (residual s.d.) or from two samples at 12 and 94 min with an error of 7 ml/min. The relative errors with MAG3 are thus comparable to those reported for similar techniques used with [131I]orthoiodohippurate, [99mTc]diethylenetriaminepentraacetic acid and [51Cr]ethylenediaminetetraacetic acid.     

Synthesis and renal excretion of technetium-99m-labeled organic cations.

Organic cations are excreted more efficiently than organic anions in uremia suggesting superiority as renal imaging agents. In this study, three 99mTc-labeled cationic cyclam complexes were synthesized and their renal clearance quantified in rats. The complexes are cleared at a rate of about 2.5-3 times that of inulin and about 60% that of p-amino-hipurate. Inhibition of 99Tc-cyclam excretion by quinine indicates transport by the organic cation process. Comparative in vivo imaging experiments demonstrated that in normal rats 99mTc-cyclam reached peak renal activity 1.8 +/- 0.6 min after injection, a value intermediate between that for [131I]OIH (1.0 +/- 0) and 99mTc-MAG3 (2.8 +/- 0.6). In rats injected with the acute nephrotoxin cisplatin, the times to peak were lengthened with the relative order being 99mTc-cyclam > 99mTc-MAG3 > [131I]OIH. The results demonstrate that cationic complexes may be useful for renal imaging diagnostic applications.     

A comparative study of renal scintigraphy and clearance with technetium-99m-MAG3 and iodine-123-hippurate in patients with renal disorders

The aim of this study was to compare kit prepared technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) with our routine radiopharmaceutical, iodine-123-hippurate our routine radiopharmaceutical, iodine-123-hippurate ([123I]OIH) for renal dynamic scintigraphy. Seventeen patients with different nephrologic disorders or hypertension were first studied with OIH and then reinvestigated with MAG3 2-8 days later. Renal MAG3 gamma camera images were almost identical with those of OIH except for higher (p less than 0.01) liver-to-background ratios at 20 min postinjection, irrespective of kidney function. Urinary peristalsis was visible longer and more clearly in the MAG3 studies. MAG3 and OIH renograms showed identical relative kidney uptake (r = 0.99), but elimination of MAG3 from the kidneys was slower (p less than 0.01). The plasma clearance of MAG3 was lower than that of OIH, but correlated (r = 0.92) significantly. The plasma distribution volume and content in blood cells was lower (p less than 0.01), but the binding of MAG3 to plasma proteins was higher, 90%, as compared with 74% for OIH, p less than 0.01. Urinary excretion expressed as a percent of the given dose 60 min after injection was the same for the two substances. Thus, there are some significant differences in the renal handling, plasma distribution, and cell penetration between MAG3 and [123I]OIH. MAG3, however, seems to have particular qualifications as a radionuclide for dynamic renal scintigraphy, especially in patients who require acute investigations or in those with low renal function.     

Technetium-99m MAG3 kit formulation: preliminary results in normal volunteers and patients with renal failure

Previous studies have shown that [99mTc]mercaptoacetyltriglycine (MAG3) purified by high performance liquid chromatography (HPLC) is a very promising new renal imaging agent which has characteristics very similar to [131I]orthoiodohippurate. An easily prepared kit formulation has been developed and evaluated in ten normal volunteers and three patients on hemodialysis. The average radiochemical purity was 96.6%. There were no adverse reactions. In the volunteers, the relative uptake +/- 1 s.d. was 49.1% +/- 2.6% for the right kidney and 50.9% +/- 2.6% or the left kidney. Urine activity was 71.4% +/- 6.4% of the injected dose at 30 min and 94.4% +/- 2.2% at 180 min. The 60-min plasma clearance was 340.0 +/- 79.0 ml/min and the volume of distribution was 5.15 +/- 1.1I. Approximately 0.5% of the injected dose was present in the gallbladder at 30-60 min postinjection. Gut activity was not present 30-60 min postinjection but reached 1% of the injected dose by 3 hr. In the hemodialysis patients, approximately 1% of the injected dose was present in the gallbladder and 0.5% in the gut at 30-60 min; gut activity increased to approximately 5% at 3 hr. In summary, results using the kit formulation compare favorably to previously published data using the HPLC purified material. Based on these preliminary results, the kit formulation is expected to have widespread clinical utility.     

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.     

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.     

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.     

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.     

Technetium-99m-MAG3 versus iodine-123-OIH: renal clearance and distribution volume as measured by a constant infusion technique.

The renal clearance and distribution volume of 99Tc-mercaptoacetyltriglycine (MAG3) and 123I-o-iodohippurate (OIH) were determined separately in six normal male volunteers using the constant infusion clearance technique in order to validate single injection clearance techniques and subsequently the normal values for these parameters. MAG3 renal clearance was 257 +/- 24 ml/min/1.73 m2, compared to the OIH clearance of 556 +/- 46 ml/min/1.73 m2 resulting in a MAG3/OIH clearance ratio of 0.47 +/- 0.06. The MAG3 and OIH apparent distribution volumes at steady-state were 14.8 +/- 3.7 and 19.4 +/- 5.3 liters, respectively, the latter value approximating the extra cellular fluid volume. Urinary excretion in the 0-30-min period after intravenous administration was 64.4 and 70.2% for MAG3 and OIH, respectively. This investigation revealed some significant differences in the normal values of the renal clearance and distribution volume of MAG3 compared with other studies.