Biological distribution of 99mTc-labeled YIGSR and IKVAV laminin peptides in rodents: 99mTc-IKVAV peptide localizes to the lung.

Two laminin-derived peptides containing either YIGSR or IKVAV (single amino acid code) sequences were radiolabeled with 99mTc and their biological distribution evaluated in rodents. Both 99mTc-peptides cleared rapidly from the circulation though the kidney, and to a lesser extent, through the liver. 99mTc-YIGSR peptide did not accumulate in any organ examined in normal, tumored, and emphysemic mice. The 99mTc-IKVAV peptide localized within 10 min to the lung of normal animals, resulting in lung-to-blood ratios of approximately 23:1. The 99mTc-IKVAV peptide localized to lung after submicron filtration and after intraperitoneal injection, suggesting that particulates do not major role in localization. Pre-incubation of 99mTc-IKVAV peptide in whole blood decreased lung localization, suggesting that margination of radiolabeled cells does not play a major role in the lung localization. When 99mTc-IKVAV was injected into mice with tumored lungs (melanoma), the lung uptake was markedly increased (up to 20% injected dose higher than control lungs) at all time points examined (10, 30, and 120 min). When 99mTc-IKVAV was injected into mice with genetic emphysema, the lung uptake was markedly decreased at all time points. The localization of the 99mTc-IKVAV-containing peptide to the lung is consistent with a receptor-based mechanism.

Renal artery stenosis and ischemia. Effect on renal blood flow and extraction fraction.

The clearance of [131I]orthoiodohippurate and 99mTc-mercaptoacetyltriglycine provide a measure of effective renal plasma flow, yet these clearances are proportional to renal plasma flow only if the extraction fraction remains constant. To determine the effect of unilateral renal artery stenosis, captopril, renal ischemia, and partial renal vein occlusion on renal blood flow and the extraction fraction of [131I]orthoiodohippurate, 99mTc-mercaptoacetyltriglycine, and [125I]iothalamate, we conducted a series of constant infusion studies in Sprague-Dawley rats. Renal artery flow reduction of approximately 70% decreased the extraction fraction of all three agents (P < or = .05). Captopril had no effect on extraction fraction in controls, but it produced a further decrease in extraction fraction of 99mTc-mercaptoacetyltriglycine and [131I]orthoiodohippurate in rats with renal artery stenosis (P < or = .05). Ischemia resulted in a 16% decrease in flow (P < .01) but a much larger (47% to 65%) decrease in extraction fraction of all three agents (P < .002). Partial renal vein occlusion also decreased the extraction fraction of all three agents (P < or = .05). The changes in extraction fraction imply that the clearances of [131I]orthoiodohippurate and 99mTc-mercaptoacetyltriglycine in disease states may not be proportional to renal plasma flow. Furthermore, in rats with renal artery stenosis it appears that renal blood flow must fall below a critical threshold of approximately 58% before extraction fraction decreases; as renal blood flow is further reduced below this threshold, there is a corresponding reduction in extraction fraction (P < .01).

Effect of advanced age on p-aminohippurate-induced inhibition of renal tubular secretion in male Fischer 344 rats.

The effect of aging on glomerular filtration, effective renal plasma flow and on the responsiveness of the renal tubular anion secretory system to inhibition by 4-aminobenzoylglycine (p-aminohippurate, PAH) was examined in young (5-month) and old (22-month) Fischer 344 male rats. Plasma clearance, protein binding and renal extraction of [131I]o-iodohippurate, [125I]iothalamate and HPLC-purified [99mTc]mercaptoacetyltriglycine (MAG3), were used as in vivo probes of renal function. The effect of advanced age, without concomitant PAH, on the disposition of these markers was initially determined in ketamine anesthetized, temperature-maintained male rats, ages 5, 14 and 22 months by means of constant infusion clearance studies. Aging per se decreased (P less than 0.05) the kidney-weight normalized or body weight-normalized GFR and effective renal plasma flow rates. GFR values averaged 1.67, 1.43 and 1.32 ml/min per g kidney for the 5-, 14- and 22-month-old rats, respectively. Kidney- or body weight-normalized clearances of MAG3 and o-iodohippurate showed similar (25-27%) decreases, whereas the absolute values (ml/min) for GFR, o-iodohippurate and MAG3 clearance rates were not altered by aging. The effective filtration fraction, extraction ratio and plasma protein binding were also unchanged by advanced age. Overall, the age-related decreases in renal function were minimal in Fischer-344 rats, compared to other species. Differences in data normalization, species and gender account, in part, for discrepancies observed when comparing results in different studies on the effects of advanced age on renal function. Subsequently, we examined the effect of aging on the renal responsiveness to inhibition of tubular anion secretion using constant rate PAH infusion studies, adjusted for age-related changes in renal function. Aging did not alter PAH-induced inhibition of iodohippurate secretion. Inhibition of MAG3 elimination was more pronounced in the old rats compared to the young controls.

Tissue distribution properties of technetium-99m-diamide-dimercaptide complexes and potential use as renal radiopharmaceuticals.

A series of new ligands and the corresponding technetium-99m chelates based on diamide dimercaptide donor groups were synthesized as derivatives of technetium-99m 1,2-bis(2-thioacetamido)ethane, a complex shown to be excreted by renal tubular secretion. Chelation with 99mTc resulted in single radiochemical products or the expected numbers of stereoisomers. They were purified by high-performance liquid chromatography (HPLC) and evaluated in mice as potential renal tubular function agents. The in vivo properties were sensitive to the presence of functional groups, the positional isomerism of the carboxylate group functionality, and the chelate ring stereochemistry of the ligand. The presence of methyl groups slowed renal transit and decreased renal specificity. Cyclohexyl rings fused to the ethylene bridge of the center chelate ring decreased renal excretion while aromatic rings essentially abolished renal excretion. Slow hepatobiliary clearance was observed as an alternate mode of excretion. Polar groups, such as hydroxyl, carboxylate, and carboxamide, increased renal excretion rates and specificity in a stereochemically dependent manner. 99mTc chelates of 1,3-bis(2-thioacetamido)-2-hydroxypropane, 3,4-bis(2-thioacetamido)butanoate and 1,8-dimercapto-2,7-dioxo-3,6-diazanonanoate were identified as promising new renal radiopharmaceuticals.

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.

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.

Radiation dosimetry for technetium-99m-MAG3, technetium-99m-DTPA, and iodine-131-OIH based on human biodistribution studies.

Radiation dose estimates were calculated for the renal agents 99mTc-DTPA, 99mTc-MAG3, and 131I-OIH from biodistribution data gathered in groups of healthy human volunteers. Biokinetics were evaluated by Anger camera imaging, blood sampling, and urine collection and counting. Collected data were fit to four- or five-compartmental models using the CONversational Simulation, Analysis, and Modeling (CONSAM) software. Radiation dose estimates were performed using standard MIRD techniques. Average residence times in urinary bladder, kidney, and remainder of the body were used to predict radiation dose equivalents and effective dose equivalents for the three agents. Doses for DTPA and MAG3 were very similar and much lower on a per unit injected activity than OIH. The effective dose equivalents were 3.3 mSv/370 MBq for 99Tc-DTPA, 3.7 mSv/370 MBq for 99mTc-MAG3, and 0.99 mSv/11.1 MBq for 131I-OIH for bladder voiding every 4.8 hr; effective dose equivalents were 2.0 mSv/370 MBq for 99mTc-DTPA, 1.5 mSv/370 MBq for 99mTc-MAG3, and 0.28 mSv/11.1 MBq for 131I-OIH for bladder voiding at 30 min and then every 4.0 hr. Patients should void at the conclusion of the study, as early voiding can reduce the gonadal radiation dose by a factor of 2 to 3.

Prospective validation of a single sample technique to determine technetium-99m-MAG3 clearance.

Technetium-99m-MAG3 clearance is proportional to OIH clearance and can be used directly as a measure of renal function. Multiple plasma sample, two-compartment clearance data from three studies were recently pooled to develop a single-sample regression equation for determining the clearance of 99mTc-MAG3. To test this published equation, a prospective study was conducted in 34 patients with a wide range of renal function. Multiple plasma samples were obtained from 9 to 60 min following the bolus injection of 99mTc-MAG3 and the clearances were calculated based on a single injection, two-compartment model. Clearances were also calculated using a single 43-min plasma sample and the published regression equation. There was an excellent correlation (r = 0.976) between the two clearances; the slope of the regression line was 1.01 with an intercept of -26.6; the standard error of the estimate was 24 ml/min. In conclusion, the current regression equation provides a good estimate of 99mTc-MAG3 clearance.

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.

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.

Effect of protein binding on renal extraction of 131I-OIH and 99mTc-labeled tubular agents.

UNLABELLED: The clearance of 99mTc-mercaptoacetyltriglycine (MAG3) is less than the clearances of o-131I-iodohippurate (OIH) and 99mTc-labeled DD- and LL-ethylenedicysteine (EC). This difference could be associated with the lower affinity of MAG3 for the tubular transport receptor, but MAG3 is more highly protein bound than OIH and the EC isomers; protein binding could also be an important factor governing tubular extraction. To separate the effects of protein binding from tubular receptor affinity, the extraction fractions (EFs) of MAG3, OIH, and the DD, LL, and DL isomers of 99mTc-EC were measured in an isolated perfused rat kidney model using a protein-free perfusate and perfusates containing bovine serum albumin. METHODS: The right kidney was removed from the rat and perfused with modified Krebs-Henseleit buffers containing 7.5 or 2.5 g/dL bovine serum albumin or a protein-free perfusate. OIH was coinjected into the renal artery with each of the 99mTc-tracers. Protein binding was measured in each of the perfusates, and the venous outflow was collected to determine the EF. RESULTS: The protein binding of MAG3 in the albumin perfusates ranged from 87% to 95%, significantly higher than the 20%-34% range of protein binding observed with the three EC complexes (P < 0.05). In the 2.5 g/dL albumin perfusate, the EF of MAG3 was 44%, significantly less than the 57%-77% EF of the three EC complexes; in the 7.5 g/dL perfusate, the MAG3 EF fell to 18% versus 39%-45% for the EC complexes (P < 0.05). However, in the protein-free perfusate, the EF of MAG3 was 64%, equal to or higher than the 46%-62% EF of the three EC complexes. CONCLUSION: Protein binding modulates the tubular extraction of renal tracers. Protein binding and receptor affinity must be considered in the design of future renal radiopharmaceuticals as well as radiopharmaceuticals targeting other receptors.

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.

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.

Evaluation of technetium-99m-triamide-mercaptide complexes designed to identify properties favoring renal tubular transport.

UNLABELLED: To aid in the design of an improved 99mTc-labeled renal agent, several new [99mTcO(MAG3)]2- analogs were synthesized to determine the effects of varying the position and chemical form of the terminal charged group on renal clearance. METHODS: Clearance, extraction efficiency and plasma protein binding were measured in six Sprague-Dawley rats per complex for ortho, meta and para isomers of [99mTcO(MAG2-ABA)]2-, with MAG2- = mercaptoacetylglycylglycyl- and ABA = aminobenzoate; [99mTcO(MAG2-pASA)]2-, with pASA = p-aminosalicylate; [99mTcO(MAG2-AMS]2-, with AMS = aminomethylsulfonate; and [99mTcO(MAG2-AMP]3-, with AMP = aminomethylphosphonate. For agents with relatively poor clearances, hepatobiliary excretion was evaluated by using a camera-based method. RESULTS: The clearances of the ortho, meta and para isomers of [99mTcO(MAG2-ABA)]2- were 17%, 20% and 59% of those of OIH, respectively. The clearances of [99mTcO(MAG2-pASA)]2-, [99mTcO(MAG2-AMS)]2- and [99mTcO(MAG2-AMP)]3- were 32%, 46% and 39% those of OIH, respectively. CONCLUSION: Optimal tubular transport appears to require a terminal anionic group; a planar carboxylate is preferred over nonplanar -SO3- or -PO3(2-) substituents, suggesting that the smaller size and/or planar shape of the carboxylate group are probably more important than the total charge or charge distribution. Optimal transport also appears to depend on the oxo-carboxylate conformation (syn or anti) and the oxo-carboxylate distance, although these relationships can be modulated by steric interactions. These structure-distribution relationships are important factors to consider in the future design of renal radiopharmaceuticals.

Comparison of technetium-99m-ll-EC isomers in rats and humans.

UNLABELLED: Technetium-99m-L,L-ethylenedicysteine (99mTc-LL-EC) is a new renal imaging agent with pharmacokinetic properties reported to be slightly superior to those of 99mTc-mercaptoacetyltriglycine (99mTc-MAG3); however, to better define the potential of the enantiomer 99mTc-DD-EC and the diastereomer 99mTc-DL-EC as renal imaging agents, we compared the three EC stereoisomers with 131I-orthoiodohippurate (OIH) in a series of rats and humans. METHODS: Each 99mTc-EC stereoisomer was coinjected with OIH in six Sprague-Dawley rats for measurements of clearance and extraction fraction. Each stereoisomer was also coinjected with OIH in three human volunteers followed by sequential imaging, plasma clearance measurements and timed urine collections. RESULTS: Technetium-99m-DD-EC had the highest clearance and extraction efficiency in rats (p < or = 0.02). In humans, image quality was good with all three agents. The clearance ratio (EC/OIH) was 82% +/- 8% for 99mTc-DD-EC compared to 70% +/- 3% and 40% +/- 5% for 99mTc-LL-EC and 99mTc-DL-EC, respectively. Technetium-99m-DD and 99mTc-LL-EC were excreted more rapidly than 99mTc-DL-EC. CONCLUSION: Technetium-99m-DD-EC has excellent imaging properties and the data suggest that its clearance may approach that of OIH more closely than any other 99mTc renal agent. A potential limitation is the fact that both 99mTc-DD and LL-EC exist in dianionic (80%) and monoanionic (20%) forms at physiological pH and it is unlikely that these two forms have the same clearance or protein binding affinity.

Measuring technetium-99m-MAG3 clearance with an improved camera-based method.

UNLABELLED: Because commercially available camera-based methods are not optimized, they fail to account for dose infiltration, table attenuation and correspondence between time of injection and starting the camera. We have developed a more optimized technique to calculate camera-based clearances and applied this technique in the design of a camera-based clearance method for 99mTc-MAG3. METHODS: Technetium-99m-MAG3 scintigraphy was performed in 20 patients who had varying degrees of renal function. Data were acquired posteriorly in supine patients at 2 sec/frame for 24 frames, 15 sec/frame for 16 frames and 30 sec/frame for 40 frames. Background correction was performed using an automated elliptical region of interest. Renal depth was estimated using improved regression equations and an empirically determined attenuation coefficient derived from phantom studies. Corrections were made for table attenuation and time discrepancies between dose injection and starting the camera. The percent injected dose in the kidney at 1-2, 1-2.5 and 2-3 min postinjection and the percent injected dose at those time periods corrected for body surface area were correlated with MAG3 clearance based on a single injection, two-compartment model. RESULTS: There was high correlation between the percent injected dose in the kidney at all three time periods and the multisample clearance. Correcting for body surface areas significantly improved the correlation coefficients. Consequently, regression equations were developed to predict multisample clearance based on percent dose and body surface area. CONCLUSION: The optimization features described in this method should improve precision when sequential studies are conducted in the same patient.

Evaluation of the hepatobiliary excretion of technetium-99m-MAG3 and reconstitution factors affecting radiochemical purity.

UNLABELLED: Technetium-99-MAG3 is a renal tubular function agent. However, sporadic liver and gallbladder visualization have raised questions about kit stability, impurities and nonrenal routes of excretion. To address these issues, studies were conducted to optimize the labeling efficiency of the TechneScan MAG3 kit and to evaluate the hepatobiliary excretion of the MAG3 complex. METHODS: Thirty-six vials of the commercial formulation of 99mTc-MAG3 were prepared according to manufacturer's instructions and evaluated for radiochemical purity using two methods: a combination of high-performance liquid chromatography and paper chromatography (HPLC/PC); and the manufacturer's miniature chromatography system (Sep-Pak procedure). RESULTS: The labeling efficiency was significantly higher when the kit was reconstituted with 10 ml (96.6%) of saline versus 5 ml (91.4%) (p < 0.01). The radiochemical purity of the kits remained stable for up to 6 hr, but the purity determined by Sep-Pak averaged 2.5% higher than that determined by HPLC procedures (p < 0.01). Rat studies to evaluate renal and hepatobiliary elimination of MAG3 showed no difference in the %ID excreted into the urine by 60 min in all groups of animals studied. However, the %ID excreted into the bile was significantly higher for the kit formulation than the HPLC-purified MAG3, 9.9% versus 6.6% (p = 0.0475). CONCLUSION: The radiochemical purity of the TechneScan MAG3 kit can be improved by reconstituting with larger volumes. In addition, the studies in rats suggest that fasting or kit impurities may be a contributing factor to increased hepatobiliary visualization in patient studies.

Synthesis and evaluation of [18F]1-amino-3-fluorocyclobutane-1-carboxylic acid to image brain tumors.

UNLABELLED: We have developed a new tumor-avid amino acid, 1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC), labeled with 18F for nuclear medicine imaging. METHODS: [18F]FACBC was prepared with high specific activity (no carrier added [NCA]) and was evaluated for its potential in tumor localization. A comparative study was performed for [18F]FACBC and [18F]2-fluorodeoxyglucose (FDG) in which the uptake of each agent in 9L gliosarcoma (implanted intracerebrally in Fisher 344 rats) was measured. In addition, the first human PET study of [18F]FACBC was performed on a patient with residual glioblastoma multiforme. Quantitative brain images of the patient were obtained by using a Siemens 921 47-slice PET imaging system. RESULTS: In the rat brain, the initial level of radioactivity accumulation after injection of [18F]FACBC was low (0.11 percentage injected dose per gram [%ID/g]) at 5 min and increased slightly to 0.26 %ID/g at 60 min. The tumor uptake exhibited a maximum at 60 min (1.72 %ID/g), resulting in a tumor-to-brain ratio increase of 5.58 at 5 min to 6.61 at 60 min. In the patient, the uptake of [18F]FACBC in the tumor exhibited a maximum concentration of 146 nCi/mL at 35 min after injection. The uptake of radioactivity in the normal brain tissue was low, 21 nCi/mL at 15 min after injection, and gradually increased to 29 nCi/mL at 60 min after injection. The ratio of tumor to normal tissue was 6 at 20 min after injection. The [18F]FACBC PET scan showed intense uptake in the left frontal region of the brain. CONCLUSION: The amino acid FACBC can be radiofluorinated for clinical use. [18F]FACBC is a potential PET tracer for tumor imaging.

Technetium-99m-sulfur colloid for lymphoscintigraphy: effects of preparation parameters.

UNLABELLED: There has been a resurgence in the use of lymphoscintigraphy for the external detection of lymph nodes for metastatic melanoma and breast tumors. Technetium-99m-antimony trisulfide colloid was the radiopharmaceutical developed for this procedure and was found to have a narrow distribution of small particles, 0.003-0.03 microns, but it was never approved by the FDA. Technetium-99m-sulfur colloid also forms particles and this article reports on the effects different preparation parameters have on its particle size distribution and stability. METHODS: Four groups of kits were evaluated, kits which utilized: (a) a reduced heating protocol with a new 99mTc-elution, (b) a reduced heating protocol with an old 99mTc-elution, (c) a prolonged heating protocol with a new 99mTc-elution and (d) a prolonged heating protocol with an old 99mTc-elution. The particle size distribution and the stability of the different 99mTc-sulfur colloid kit preparations were evaluated over 6 hr utilizing polycarbonate filters ranging from 0.03 to 10 microns. RESULTS: In vitro studies demonstrated no significant change in the particle size distribution over a 6-hr period and all 99mTc-sulfur colloid preparations had a bimodal particle size distribution pattern. Importantly, heating the kit for shorter periods of times utilizing [99mTc]pertechnetate, which had a longer ingrowth of [99mTc]pertechnetate, produced a formulation which had the largest percentage of particles smaller than 0.03 microns. CONCLUSION: In our clinical setting, 99mTc-sulfur colloid prepared with the reduced heating protocol and utilizing [99mTc]pertechnetate, which has the highest ingrowth of [99mTc]pertechnetate has proved to be an excellent agent for lymphoscintigraphy studies. This preparation has demonstrated rapid movement of the particles from the primary site to the lymph nodes in over 97% (106/109) of the patients we have studied.

Biodistribution and radiation dosimetry of the dopamine transporter ligand.

UNLABELLED: 18F-labeled 2 beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(-2-fluoroethyl)nortropane ([18F]FECNT) is a recently developed dopamine transporter ligand with potential applications in patients with Parkinson's disease and cocaine addiction. METHODS: Estimates of the effective dose equivalent and doses for specific organs were made using biodistribution data from 16 Sprague-Dawley rats and nine rhesus monkeys. PET images from two rhesus monkeys were used to calculate the residence time for the basal ganglia. The computer program MIRDOSE3 was used to calculate the dosimetry according to the methodology recommended by MIRD. RESULTS: The basal ganglia were the targeted tissues receiving the highest dose, 0.11 mGy/MBq (0.39 rad/mCi). The effective dose equivalent was 0.018 mSv/MBq (0.065 rem/mCi), and the effective dose was 0.016 mSv/MBq (0.058 rem/mCi). CONCLUSION: Our data show that a 185-MBq (5-mCi) injection of [18F]FECNT leads to an estimated effective dose of 3 mSv (0.3 rem) and an estimated dose to the target organ or tissue of 19.4 mGy (1.93 rad).