Next generation of radiotracers for sentinel lymph node biopsy: What is still necessary to establish new imaging paradigms? / Nueva generación de radiotrazadores para la biopsia del ganglio centinela: ¿qué es necesario para establecer nuevos paradigmas de imagen?

Sentinel lymph node (SLN) biopsy is now the standard of care for regional staging in several solid tumors. The interstitial administration of a radiotracer around the primary tumor provide the possibility to sequentially obtain images with a gamma camera and visualize lymphatic mapping and the SLN. There is, however, a large geographical variability in those radiotracers and nanocolloids ranging from 15-100nm which are most widely employed in Europe, while filtered and unfiltered 99mTc-sulfur colloid (range 20-1000nm) is usually used in the USA with different drawbacks in its use. The new radiotracer 99mTc-Tilmanocept, designed specifically for the identification of SLNs and recently becoming commercially available in USA and Europe, appears to have the potency to overcome the shortcomings described for the conventional radiotracers used until now for SLN biopsy and at the same time to transform current imaging paradigms. After delineating the challenges for the next generation of radiotracers, this paper discusses the properties of 99mTc-Tilmanocept, its validation process for SLN biopsy and its emerging clinical applications in various malignancies.

Radiation doses in the surroundings of patients undergoing nuclear medicine diagnostic studies.

Dose rate measurements were performed at 0, 0.5, and 1 m from the external surface of 79 patients corresponding to the most frequent studies: 99mTc-cardiac with reinjection, 99mTc-cardiac single injection, 99mTc-bone scan, 99mTc-lung studies, and cardiac studies using 201Tl. Doses to staff, nearby patients, and the collective effective doses were estimated for the different working shifts and hospital areas. The estimated dose for nurses for 1 y was 518 microSv in the cardiology section and 338 microSv in the short stay section. For patients, the mean dose per stay was calculated to be 8.5 microSv in the cardiology section. The maximum dose that a patient could receive from a radioactive patient is 499 microSv for a double injection cardiac patient study. The maximum collective effective dose for the whole hospital was calculated to be 0.063 person-Sv. The probability of staff receiving doses higher than the limits for a working day is negligible. Maximum doses for staff and patients are far below dose limits for the public and therefore no additional radiological protection is needed.

Gallium-labeled deferoxamine-galactosyl-neoglycoalbumin: a radiopharmaceutical for regional measurement of hepatic receptor biochemistry.

Galactosyl-neoglycoalbumin (NGA) is a synthetic ligand to the hepatocyte-specific receptor, hepatic binding protein. In-vitro and in-vivo characterization of a chelation-based derivative of NGA, deferoxamine-galactosyl-neoglycoalbumin (DF-NGA), is described. A two-step glutaraldehyde method was used to covalently couple deferoxamine (DF) to NGA. Products with an average DF-to-NGA ratio of less than 2 contained less than 3% polymeric DF-NGA. All products retained the chelator after 12 mo of storage at 4 degrees C. Gallium labeling of DF-NGA-41 (41 galactose units per HSA) with an average of 1.1 DF per NGA was quantitative within 15 min after the addition of 67Ga-citrate. The labeled product was stable for at least 24 hr. Scatchard and reverse-binding assays of 67Ga-DF-NGA-41 revealed a forward binding rate constant kb similar to that of 125I-NGA-44. The %ID of 67Ga-DF-NGA-41 in rabbit liver was approximately 90% at 10 min after injection of 1.2 x 10(-9) mole DF-NGA per kilogram of body weight. This value decreased to 40% at a scaled molar dose of 1.2 x 10(-7) mol/kg. Biodistribution data of 67Ga-DF-NGA in rabbits was similar to 99mTc-NGA. High tissue specificity and facile labeling will make 68Ga-labeled neoglycoalbumin an ideal agent for regional measurements of receptor biochemistry in the investigational and clinical setting.

Technetium-99m galactosyl-neoglycoalbumin: preparation and preclinical studies.

Technetium-99m galactosyl-neoglycoalbumin ([Tc] NGA), a labeled analog ligand to the hepatocyte-specific receptor, hepatic binding protein (HBP), was prepared and tested for labeling yield, stability, biodistribution, toxicity, and dosimetry. The ligand was synthesized by the covalent coupling of a carbohydrate bifunctional reagent, 2-imino-2-ethyloxymethyl-1-thiogalactose, to human serum albumin. Testing in mice and rabbits revealed the product to be nontoxic and apyrogenic. Technetium labeling yields in excess of 95%, by the electrolytic method, did not alter the molecular weight profile of the neoglycoalbumin. The NGA-bound activity remained stable for at least 4 hr. Biodistribution studies in rabbits demonstrated the liver as the single focus of tracer uptake. Dosimetry was based on kinetic studies in three baboons. Absorbed doses to liver, small intestine, urinary bladder wall, and uterus were 0.089, 0.28, 0.56, and 0.88 rad/mCi, respectively. Total body, lens of the eye, red marrow, ovaries, and testes were less than 0.06 rad/mCi. High liver specificity imparted by receptor binding combined with high labeling yield, stability, acceptable dosimetry, and safety provide [Tc]NGA with the attributes required for routine clinical assessment of hepatocyte function.

Portal-Systemic shunts reduce asialoglycoprotein receptor density in rats.

UNLABELLED: The clinical usefulness of quantitative functional imaging techniques that use asialoglycoprotein receptor (ASGP-R) binding is based on the correlation between ASGP-R density and hepatic functional reserve. Portal-systemic shunting (PSS) is common in patients with cirrhosis and portal hypertension-the same group that is most frequently considered for such imaging. PSS occurs spontaneously through collateral vessels and from the creation of surgical shunts or placement of transjugular intrahepatic portal-systemic shunts (TIPS). Understanding the physiologic relationship between PSS and ASGP-R activity may aid in the interpretation of quantitative clinical imaging. This study was conducted to determine the relationship between PSS and ASGP-R density in the absence of parenchymal disease. METHODS: Sprague-Dawley rats with end-to-side portal-systemic shunts and sham-operated control rats were imaged with 99mTC-diethylenetriaminepentaacetic acid galactosyl-neoglycoalbumin. Pharmacokinetic modeling of the liver and heart time-activity data was used to measure ASGP-R concentration, as well as hepatic plasma volume and flow. RESULTS: The mean ASGP-R density (nmol/g of liver) was significantly decreased in the shunted rats. Blood ammonia was significantly elevated, whereas hepatic plasma flow, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase levels were unaltered. Liver histology was normal in both groups. CONCLUSION: A significant change in the ASGP-R density occurs with PSS in the absence of parenchymal disease. PSS appears to be an independent variable affecting ASGP-R activity. This could prove clinically important during interpretation of quantitative imaging from patients with varying degrees of PSS based on underlying disease or the presence of a surgical shunt or TIPS device.

Kinetic sensitivity of a receptor-binding radiopharmaceutical: technetium-99m galactosyl-neoglycoalbumin.

Kinetic sensitivity is the ability of a physiochemical parameter to alter the time-activity curve of a radiotracer. The kinetic sensitivity of liver and blood time-activity data resulting from a single bolus injection of [99mTc]galactosyl-neoglycoalbumin [( Tc]NGA) into healthy pigs was examined. Three parameters, hepatic plasma flow scaled as flow per plasma volume, ligand-receptor affinity, and total receptor concentration, were tested using [Tc]NGA injections of various molar doses and affinities. Simultaneous measurements of plasma volume (iodine-125 human serum albumin dilution), and hepatic plasma flow (indocyanine green extraction) were performed during 12 [Tc]NGA studies. Paired data sets demonstrated differences (P(chi v2) less than 0.01) in liver and blood time-activity curves in response to changes in each of the tested parameters. We conclude that the [Tc]NGA radiopharmacokinetic system is therefore sensitive to hepatic plasma flow, ligand-receptor affinity, and receptor concentration. In vivo demonstration of kinetic sensitivity permits delineation of the physiologic parameters that determine the biodistribution of a radiopharmaceutical. This delineation is a prerequisite to a valid analytic assessment of receptor biochemistry via kinetic modeling.

Receptor measurements via Tc-GSA kinetic modeling are proportional to functional hepatocellular mass.

UNLABELLED: Kinetic modeling of 99mTc-diethylenetriaminepentaacetic acid galactosyl human serum albumin (Tc-GSA) measures the total amount of asialoglycoprotein receptor within a subject's liver. This study tested the hypothesis that the amount of asialoglycoprotein receptor measured by Tc-GSA modeling provides a valid index of functional liver mass. METHODS: Twenty-two patients with cirrhosis, 18 patients with chronic hepatitis, and 9 patients with normal liver parenchyma were studied with Tc-GSA using a 30-min dynamic imaging protocol. The total amount of hepatic receptor was measured by kinetic modeling of the Tc-GSA time-activity data. The total number of viable hepatocytes was calculated using standard morphometric measurements of liver biopsy samples and liver volume measurements through CT. RESULTS: The total receptor amount strongly correlated with the total hepatocyte number (r = 0.803; P < 0.0001). CONCLUSION: Tc-GSA measurement of the total receptor amount is proportional to the number of viable hepatocytes and therefore provides a valid assessment of functional liver mass.

Validation of in vivo receptor measurements via in vitro radioassay: technetium-99m-galactosyl-neoglycoalbumin as prototype model.

Hepatic binding protein (HBP) is a hepatocyte-specific receptor for serum asialoglycoproteins. The receptor also recognizes a synthetic glycoprotein that has been developed as a radiopharmaceutical, technetium-99m-galactosyl-neoglycoalbumin (99mTc-NGA). This report describes the correlation between receptor parameters measured in vivo via kinetic modeling of 99mTc-NGA and those measured by in vitro radioassay of biopsied liver tissue. Eleven patients with diffuse hepatic disease underwent percutaneous liver biopsy followed by a 99mTc-NGA functional imaging study. In vivo measurements of HBP quantity Ro and forward binding rate constant kb obtained from the kinetic analysis of 99mTc-NGA liver and blood time-activity data were compared to total receptor quantity and the HBP-99mTc-NGA association constant KA as measured by Scatchard binding assay of the biopsied tissue. The correlation coefficients between in vivo and in vitro measurements were 0.73 (df = 8, p = 0.015) and 0.98 (df = 8, p less than 0.01) for Ro and kb, respectively. The in vivo measurements of HBP biochemistry via kinetic analysis of the radiopharmaceutical time-activity data reflect the average concentration and affinity of the receptor. This study further substantiates the validity of 99mTc-NGA as a quantitative probe for the HBP receptor.

Sentinel node imaging via a nonparticulate receptor-binding radiotracer.

UNLABELLED: Technetium-99m-labeled polydiethylenetriamine pentaacetic acid polymannosyl polylysine (DTPA-man-PL) was synthesized and tested for lymph node scintigraphy by subcutaneous administration. The agent was designed for receptor-mediated uptake by mannosebinding protein, which resides on the plasma membrane of reticuloendothelial cells. METHODS: Subcutaneous injections of a 99mTc-labeled agent having 18 DTPA and 82 mannosyl groups attached to a polylysine of 100 units ([99mTc]DTPA18-man82-PL100) were made at the level of the metacarpus and metatarsus of three healthy rabbits. Images were acquired at 1, 6, 12 and 24 hr. Popliteal and axillary nodes were then assayed for percent of injected dose (%ID). A negative control study was performed in three normal rabbits with [99mTc]DTPA18-PL100. RESULTS: Significant differences in mean 24-hr %ID between the receptor specific and nonspecific agents were observed for both the popliteal (p < 0.006) and axillary (p < 0.012) nodes. Popliteal percent injected dose at 24 hr was 3.00 +/- 0.72% for [99mTc]DTPA-man-PL and 0.13 +/- 0.08% for [99mTc] DTPA-polylysine. Axillary accumulation at 24 hr was 2.84 +/- 0.83% for [99mTc]DTPA-mannosyl-polylysine and 0.22 +/- 0.12% for [99mTc] DTPA-polylysine. Percent injected dose of the receptor-specific agent was highest (4%) during the 6-hr scan. Accumulation of the nonspecific agent by the popliteal and axillary nodes at 6-hr postinjection was approximately 0.5%. CONCLUSION: This study provides proof of principle for lymphoscintigraphy by receptor-mediated delivery of a nonparticulate imaging agent.

Automatic preparation of radiopharmacokinetic data for in vivo estimation of receptor biochemistry.

UNLABELLED: We present a fully automated region of interest (ROI) and motion correction program for the generation of heart and liver time-activity data resulting from a hepatic functional imaging study using [99mTc-]galactosyl-neoglycoalbumin (99mTc-NGA). METHODS: The program automatically draws heart and liver ROI and corrects for lateral movement of the subject. Eighty-four 99mTc-NGA studies, consisting of 32 healthy subjects and 52 patients with liver disease, were processed and submitted to an automated kinetic analysis that estimates the subject's asialoglycoprotein receptor concentration [R]o. RESULTS: When compared to time-activity data generated by operator-drawn ROIs without motion correction, the average reduced Chi-square of the kinetic analysis decreased significantly (p < 0.001) from 2.20 to 1.37 and the number of studies that satisfied quality control increased from 74 to 81 studies. Receiver operating characteristic of [R]o resulted in greater detectability (0.984 +/- 0.012 compared with 0.965 +/- 0.020) when automatic ROI generation was employed. Using the test criteria of 0.65 microM, the sensitivity of [R]o increased from 0.88 to 0.92 and the specificity increased from 0.96 to 0.97. CONCLUSION: Automated definition of liver and heart ROIs with motion correction, that reduces observational noise, increased the success rate of the radiopharmacokinetic analysis from 88% to 96%.

A synthetic macromolecule for sentinel node detection: (99m)Tc-DTPA-mannosyl-dextran.

UNLABELLED: We report the synthesis and preliminary biologic testing of a synthetic macromolecule, (99m)Tc-diethylenetriaminepentaacetic acid (DTPA)--mannosyl-dextran, for sentinel node detection. METHODS: Synthesis started with a 2-step process that attaches a high density of amino-terminated leashes to a dextran backbone. Allyl-bromide was reacted with pharmaceutical-grade dextran to yield allyl-dextran. After diafiltration with water, filtration, and lyophilization, the product was reacted with aminoethanethiol and ammonium persulfate. The resulting amino-conjugated dextran was dialyzed, filtered, and lyophilized. The mixed anhydride method was used to attach DTPA; after dialysis, filtration, and lyophilization, 2-imino-2-methoxyethyl-1-D-mannose was used to attach the receptor substrate. The molecular diameter was measured by dynamic light scattering. Amino, mannose, and DTPA densities were measured by trinitrobenzene sulfonate assay, sulfuric acid/phenol assay, and inductively coupled plasma spectroscopy of gadolinium-DTPA-mannosyl-dextran, respectively. Receptor affinity was measured by Scatchard assay of rabbit liver. Axillary, popliteal, and iliac lymph nodes and each injection site were assayed for radioactivity at 1 and 3 h after injection of approximately 3.7 MBq (0.050 mL) (99m)Tc-DTPA-mannosyl-dextran (0.22 nmol) or filtered (99m)Tc-sulfur colloid into the foot pads. Four animals were studied at each time point. RESULTS: DTPA-mannosyl-dextran had a molecular weight of 35,800 g/mol and a molecular diameter of 7.1 nm. The final amine, mannose, and DTPA densities were 23, 55, and 8 mol per dextran. Labeling yields were in excess of 98% and stable for 6 h. Specific activities of 74 x 10(6) GBq/mol were achieved. The equilibrium dissociation constant for binding to the mannose-terminated glycoprotein receptor was 0.12 +/- 0.07 nmol/L. The popliteal extraction at both 1 h and 3 h was significantly (P < 0.05) higher for (99m)Tc-DTPA-mannosyl-dextran (90.1% +/- 10.7% and 97.7% +/- 2.0%, respectively) than for filtered (99m)Tc-sulfur colloid (78.8 +/- 6.5 and 67.4% +/- 26.8%, respectively). (99m)Tc-DTPA-mannosyl-dextran exhibited significantly faster injection site clearance than did filtered (99m)Tc-sulfur colloid. The (99m)Tc-DTPA-mannosyl-dextran percentage injected dose (%ID) for the front and rear paws was 52.6 +/- 10.5 and 52.3 +/- 8.0 at 1 h and 45.7 +/- 8.5 and 43.6 +/- 8.2 at 3 h after administration. The filtered (99m)Tc-sulfur colloid %ID for the front and rear paws was 70.4 +/- 11.0 and 66.3 +/- 15.1 at 1 h and 55.5 +/- 7.8 and 66.9 +/- 8.5 at 3 h. Lymph node accumulation of each agent at either 1 or 3 h was not significantly different. CONCLUSION: (99m)Tc-DTPA-mannosyl-dextran is a receptor-based sentinel node radiotracer that exhibits the desired properties of rapid injection site clearance and low distal node accumulation. This molecule is the first member of a new class of diagnostic agents based on a macromolecular backbone with a high density of sites for the attachment of substrates and imaging reporters.

Measurement of receptor concentration and forward-binding rate constant via radiopharmacokinetic modeling of technetium-99m-galactosyl-neoglycoalbumin.

Technetium-99m-galactosyl-neoglycoalbumin (99mTc-NGA) is a synthetic ligand to the hepatocyte receptor, hepatic binding protein (HBP). A five-state mathematical model containing a bimolecular chemical reaction was utilized for quantitative estimation of the following physiologic and biochemical parameters: extrahepatic plasma volume Ve; hepatic plasma flow F and volume Vh; receptor-ligand forward-binding rate constant kb and reaction volume Vr; and receptor concentration [R]o. Nine normal subjects were studied. Given (a) liver and heart time-activity data, (b) the patient's weight, height, and hematocrit, (c) the fraction of injected dose in a 3-min blood sample, and (d) the amount and galactose density of the NGA dose, a computer program executed a curve-fit to the kinetic model. Systematic error, as measured by reduced chi-square, ranged from 1.43 to 2.56. Based on the nine imaging studies, the mean and relative error of each parameter were: [R]o, 0.813 +/- (0.11) microM; kb, 2.25 +/- (0.15) microM-1 min-1; F, 0.896 +/- (0.20) liter/min; Ve, 1.67 +/- (0.27) liter; and Vh, 0.228 +/- (0.22) liter. Two unique features of 99mTc-NGA radiopharmacokinetic systems permit the simultaneous estimates of receptor quantity, ligand affinity, and hepatic plasma flow. The first is the ability to administer a quantity of ligand capable of occupying a significant fraction of receptor; and the second is a simple model structure that conserves mass.

Diagnostic performance of a receptor-binding radiopharmacokinetic model.

UNLABELLED: The aim of this study was to determine which measurement obtained from a radiopharmacokinetic model of a receptor-binding radiotracer provides the highest diagnostic performance for the detection of diffuse hepatocellular disease. METHODS: Twenty-seven healthy subjects and 46 patients with diffuse hepatocellular disease were studied with the receptor-binding radiopharmaceutical, 99mTc-galactosyl-neoglycoalbumin. A radiopharmacokinetic model was used to produce estimates of receptor concentration [R]o, the scaled forward-binding rate constant Kb, hepatic plasma volume, Vh, extrahepatic plasma volume, Ve and hepatic plasma flow, F. Receiver operating characteristic analysis of each model estimate was conducted. RESULTS: Receptor concentration [R]o and the metrics [R]o/tbw and kb[R]o[R]o/tbw provided the best discrimination between healthy and diseased liver. The forward-binding rate constant kb and the metrics F/Ve and Vh/tbw provided no discrimination. CONCLUSION: Based on simplicity and higher measurement precision, [R]o was selected as the most accurate index of hepatic function.

Tc-99m galactosyl-neoglycoalbumin: in vitro characterization of receptor-mediated binding.

Hepatic binding protein (HBP) is a membrane receptor that binds and transports plasma glycoproteins from hepatic blood to hepatocellular lysosomes. We have characterized the in vitro binding of Tc-99m galactosyl-neoglycoalbumin (Tc-NGA), a synthetic HBP ligand, to liver membrane. Structural modifications of NGA resulted in the alteration of the equilibrium constant, KA, and the forward-binding rate constant, kb. Binding was second-order; the relative amount of membrane-bound NGA depended on the initial concentrations of ligand and membrane. Membrane displacement studies, using carrier ligands in contrast to previously bound Tc-NGA or I-NGA, correlated with the binding characteristics of a native HBP ligand, asialo-orosomucoid. We used computer simulation to study the detectability of the changes in HBP concentration at different values of kb. The simulations indicated that radiopharmacokinetic sensitivity to alterations in [HBP] should be possible using a neoglycoalbumin preparation with a carbohydrate density within the range of 15 to 25 galactose units per albumin molecule.

Recovery of hepatic asialoglycoprotein receptors after major hepatic resection.

UNLABELLED: Although morphological restoration of the hepatic mass after partial hepatectomy has been well studied, fewer reports have appeared on the change of functional hepatic capacity during liver regeneration. Asialoglycoprotein receptor (ASGP-R) is a hepatic cell surface receptor specific for galactose-terminated glycoprotein. Kinetic modeling of 99mTc-labeled diethylenetriamine pentaacetic acid-galactosyl-human serum albumin (TcGSA) time-activity data yields estimates of ASGP-R concentration [R]o and amount R0, which are directly related to functional liver mass. We have investigated the changes in ASGP-R status as well as liver volume in regenerating human liver after major hepatic resection. METHODS: Twenty-two patients (18 noncirrhotic, 4 cirrhotic) had a TcGSA study before and 3 wk after major hepatic resection, with a mean hepatic parenchymal resection rate of 36.0%. RESULTS: [R]0 was significantly decreased from 0.683+/-0.024 micromol/L to 0.565+/-0.032 micromol/L (P < 0.001) after resection. The decrease in [R]0 was more prominent in cirrhotic patients. Recovery of ASGP-R was observed as a significantly increased R0 3 wk after the operation. Subsequent (long-term) restoration of ASGP-R appeared to be slower when compared with the volume restoration. CONCLUSION: ASGP-R concentration of the liver significantly decreased after major hepatic resection. Subsequent recovery of ASGP-R amount was shown by TcGSA study. By estimating hepatic functional reserve expressed by ASGP-R amount and concentration, one may detect a delayed or impaired liver regeneration with higher sensitivity.

Technetium-99m NGA functional hepatic imaging: preliminary clinical experience.

Technetium-99m galactosyl-neoglycoalbumin ( [Tc]NGA) is a radiolabeled ligand to hepatic binding protein, a receptor which resides at the plasma membrane of hepatocytes. This receptor-binding radiopharmaceutical and its kinetic model provide a noninvasive method for the assessment of liver function. Eighteen patients were studied: seven with hepatoma, eight with liver metastases, four with cirrhosis (two had concurrent hepatoma and one chronic active hepatitis), and one patient with acute fulminant non-A, non-B hepatitis. Technetium-99m NGA liver imaging provided anatomic information of diagnostic quality comparable to that obtained with other routine imaging modalities, including computed tomography, angiography, ultrasound, and [Tc]sulfur colloid scintigraphy. Kinetic modeling of dynamic [Tc]NGA data produced estimates of standardized hepatic blood flow, Q (hepatic blood flow divided by total blood volume), and hepatic binding protein concentration, [HBP]. Clinical correlation was by classical Child-Turcotte criteria (CTC). Significant rank correlation was obtained between [HBP] estimates and CTC scores (rs = -0.72, p = 0.001). This correlation supports the hypothesis that [HBP] is a measure of functional hepatocyte mass. The combination of decreased Q and markedly reduced [HBP] may have prognostic significance; all three patients with this combination died of hepatic failure within 6 wk of imaging.

Tc-NGA imaging in liver transplantation: preliminary clinical experience.

Technetium-99m galactosyl-neoglycoalbumin (Tc-NGA) is a new liver imaging agent that binds to hepatic-binding protein, a hepatocyte-specific membrane receptor. The purpose of this study was to determine the potential of Tc-NGA imaging in clinical liver transplantation. A total of 25 studies were performed in nine patients. Imaging studies performed in the early posttransplant period in patients with good hepatic allograft function revealed diffuse patchiness in tracer distribution, a manifestation of preservation damage. Left lobar infarction was demonstrated within a few hours of ischemic injury. Right posterior segmental infarction was seen in another patient. Comparison of kinetic, clinical, and biochemical data revealed good correlation between hepatic allograft function and Tc-NGA kinetics. Major kinetic alterations were noted during periods of preservation injury, hepatic infarction, and acute rejection. These studies indicate: (1) major alterations in Tc-NGA kinetics occur during preservation injury, hepatic infarction, and acute rejection, and (2) Tc-NGA kinetic data appear to provide an accurate reflection of hepatic allograft function. Tc-NGA imaging has the advantages of being noninvasive and of utilizing standard nuclear medicine instrumentation, including portable imaging devices. In conclusion, Tc-NGA imaging provides a promising noninvasive approach for evaluation of liver function in patients undergoing hepatic transplantation.

Tc-NGA imaging in liver transplantation: preclinical studies.

Tc-99m galactosyl-neoglycoalbumin (Tc-NGA) is a new liver-imaging agent which binds to hepatic binding protein (an hepatocyte-specific membrane receptor). This study evaluated the sensitivity of Tc-NGA kinetics and imaging anatomy to pathologic states that are encountered after liver transplantation. Studies were performed in adolescent pigs under control conditions (18 studies), and after orthotopic liver transplantation (nine studies), common bile duct ligation (three studies), hepatic artery ligation (one study), and hepatic resection (two studies). Anatomic and kinetic data were analyzed. Excellent liver images and minimal kinetic changes were noted after common bile duct ligation. Marked imaging defects and major kinetic alterations were observed after hepatic artery ligation and in the presence of preservation injury. Marked depression in hepatic Tc-NGA uptake was observed during acute rejection. Minor alterations in Tc-NGA kinetics were noted after a 25% hepatectomy. These studies indicate that minimal changes in Tc-NGA uptake occur after common bile duct ligation; Tc-NGA uptake is markedly sensitive to hepatic ischemia; decreased Tc-NGA uptake occurs during acute rejection; and hepatic infarcts are demonstrated promptly after preservation injury. Thus Tc-NGA imaging provides a novel means of evaluating hepatic ischemia, hepatic preservation, and hepatic allograft rejection. Tc-NGA imaging may also provide a means of evaluating hepatic regeneration and hepatocyte retrodifferentiation during regeneration.

[(99m)Tc]MAG(3)-mannosyl-dextran: a receptor-binding radiopharmaceutical for sentinel node detection.

Technetium-99m-labeled benzoyl-mercaptoacetylglycylglycyl-glycine-mannosyl-dextran ([(99m)Tc]MAG(3)-mannosyl-dextran) is a receptor-binding radiotracer that binds to mannose-binding protein, a receptor expressed by recticuloendothelial tissue. This agent is composed of a 10.5-kilodalton molecule of dextran and multiple units of mannose, and benzoyl-mercaptoacetylglycylglycyl-glycine (BzMAG(3)). The tetraflorophenol-activated ester of BzMAG(3) and the imidate of thiomannose were used to covalently attach BzMAG(3) and mannose to an amino-terminated conjugate of dextran. This yielded a 19-kilodalton macromolecule consisting of 3 BzMAG(3) and 21 mannose units per dextran. Dynamic light scattering was used to measure a mean diameter of 5.5 nanometers for BzMAG(3)-mannosyl-dextran and 0.28 microns for filtered Tc-99m sulfur colloid. A preliminary sentinel node detection study employing right fore and hind footpad injections of [(99m)Tc]MAG(3)-mannosyl-dextran and left fore and hind footpad injections of filtered Tc-99m sulfur colloid demonstrated greater sentinel lymph node uptake by the receptor-binding agent.

Local identifiability of a receptor-binding radiopharmacokinetic system having measured parameters of known uncertainty.

Local identifiability was determined for a receptor-binding radiopharmacokinetic system that included measured parameters of known uncertainty. Healthy subjects and patients with severe liver disease were studied with [99mTc] galactosylneoglycoalbumin (TcNGA). Measurements during the 30-min dynamic imaging study included the count rate over liver and heart, the quantity of TcNGA injected Lo, and the fraction-of-injected dose per liter of sampled plasma f. Typical relative standard deviations for these measurements were 1, 0.2, and 5 percent, respectively. A four-state nonlinear model describing the hepatic and plasma time-activity data was then used to calculate the standard error se(pj) for model parameters representing receptor concentration [R]o, the TcNGA-receptor forward binding rate constant kb, extrahepatic plasma volume Ve, hepatic plasma volume Vh, and hepatic plasma flow F. Accounting for the measurement uncertainties of Lo and f did not significantly increase the standard errors for parameters [R]o, kb, Ve, Vh and F. When the relative errors of Lo and f were increased to 40%, the change in se(pj) ranged from 10 to 100%, with parameter Vh being the most sensitive. The exception was se(kb), the increase of which was less than 1%. Imaging studies with reduced [R]o, typically associated with patients with liver disease, resulted in greater increases in all estimated parameter errors except se(kb) which had a lower increase. Lastly, the error propagation introduced by direct measurement of the liver observational coefficients sigma 12 and sigma 13 was investigated by simulating changes in the relative standard deviation in parameters sigma 12 and sigma 13 from 0 to 40%. Imaging studies from healthy subjects showed no increase in se(pj).(ABSTRACT TRUNCATED AT 250 WORDS)