Phase I clinical study with different doses of 99mTc-TRODAT-1 in healthy adults.

OBJECTIVES: To study the pharmacokinetics, biodistribution, and injection doses of 99mTc-TRODAT-1 in healthy adults. METHODS: Thirty healthy individuals comprising 15 females and 15 males were randomly divided into three groups and the injection doses of 99mTc-TRODAT-1 of group 1, 2, and 3 were 370 MBq, 740 MBq, and 1110 MBq, respectively. Assessments of subjective symptoms and tests were performed before and after injection. Blood and urine collections and whole-body planar imaging were analyzed at various time points. Bilateral brain striatal SPECT images obtained at 3.5 h PI were assessed visually and semiquantitatively. RESULTS: No serious adverse events or deaths were observed in our study. The pharmacokinetic analysis showed that 99mTc-TRODAT-1 was eliminated rapidly from the circulation, with just about 4% of the injected dose remaining in blood at 1 h post-injection. The mean cumulative urinary excretion over 24 h was just 2.96 ± 0.96%ID. The time-activity curve demonstrated that the radioactivity was mainly in liver and abdomen. The highest absorbed dose was in the dose-limiting organ, liver (20.88 ± 4.45 × 10-3 mSv/MBq). The average effective dose was 5.22 ± 1.05 × 10-3 mSv/MBq. The clarity of striatal images assessed visually in group 1 was worse than that in group 2 and 3. The semiquantitative analysis showed that there were no differences in striatum/cerebellum between the three groups (group 1: 1.77 ± 0.11, group 2: 1.62 ± 0.14, and group 3: 1.75 ± 0.20; P = 0.088). CONCLUSIONS: 99mTc-TRODAT-1 was safe to use in humans and showed the status of dopaminergic neurons specifically and clearly. The injection dose we suggested was 740 MBq.

Absolute radiotracer concentration measurement using whole-body solid-state SPECT/CT technology: in vivo/in vitro validation.

The accuracy of recently approved quantitative clinical software was determined by comparing in vivo/in vitro measurements for a solid-state cadmium-zinc-telluride SPECT/CT (single photon emission computed tomography/x-ray computed tomography) camera. Bone SPECT/CT, including the pelvic region in the field of view, was performed on 16 patients using technetium-99m methylene diphosphonic acid as a radiotracer. After imaging, urine samples from each patient provided for the measurement of in vitro radiopharmaceutical concentrations. From the SPECT/CT images, three users measured in vivo radiotracer concentration and standardized uptake value (SUV) for the bladder using quantitative software (Q.Metrix, GE Healthcare). Linear regression was used to validate any in vivo/in vitro identity relations (ideally slope = 1, intercept = 0), within a 95% confidence interval (CI). Thirteen in vivo/in vitro pairs were available for further analysis, after rejecting two as clinically irrelevant (SUVs > 100 g/mL) and one as an outlier (via Cook's distance calculations). All linear regressions (R2 ≥ 0.85, P < 0.0001) provided identity in vivo/in vitro relations (95% CI), with SUV averages from all users giving a slope of 0.99 ± 0.25 and intercept of 0.14 ± 5.15 g/mL. The average in vivo/in vitro residual difference was < 20%. Solid-state SPECT/CT imaging can reliably provide in vivo urinary bladder radiotracer concentrations within approximately 20% accuracy. This practical, non-invasive, in vivo quantitation method can potentially improve diagnosis and assessment of response to treatment. Graphical abstract.

Scintigraphic assessment of renal function in steel plant workers occupationally exposed to lead.

OBJECTIVES: Occupational exposure to lead may produce kidney damage, but existing data on the dose range associated with nephrotoxicity are inconclusive. We here assessed renal function under conditions of low to moderate lead exposure using renal scintigraphy. METHODS: Fifty-three male foundrymen (exposed group) and fourty male office workers (control group) from a steel plant were included in the study. Glomerular and tubular renal function were assessed by means of (99m)Tc-DTPA and (99m)Tc-EC clearance, respectively. Urinary markers of glomerular dysfunction (albumin) and tubular damage (α1-microglobulin (α1M), ß2-microglobulin (ß2M), retinol-binding protein (RBP), N-acetyl-ß-glucosaminidase (NAG) activity) were determined using latex beads tests or colorimetry. The lead concentration in blood was measured with atomic absorption spectrometry. RESULTS: The blood lead concentrations were 145.8 (121.3-175.3) and 39.3 (35.1-44.1) µg/l (geometric mean, 95(th) CI, p<0.001) in the exposed and control groups, respectively. Subjects exposed to lead presented with increased (99m)Tc-DTPA clearance (158.3 (148.4-168.8) vs. 135.9 (127.9-144.4) ml/min; p<0.01) and urinary albumin excretion (7.61 (6.28-9.22) vs. 4.78 (4.05-5.65) mg/g creatinine; p<0.001). (99m)Tc-EC clearance and excretion of α1M, ß2M, RBP and NAG were not significantly different between the groups. Significant correlations between (99m)Tc-DTPA clearance and blood lead concentrations (r=0.45; p<0.01) and between urinary albumin excretion and blood lead concentrations (r=0.71; p<0.001) were noted. CONCLUSIONS: Use of renal scintigraphy in present study revealed measurable alterations of renal function under the conditions of low-level lead exposure and suggest that increased glomerular filtration may be an early indicator of kidney damage in subjects occupationally exposed to lead.

(99m)Tc(CO)3(NTA): a (99m)Tc renal tracer with pharmacokinetic properties comparable to those of (131)I-OIH in healthy volunteers.

UNLABELLED: Studies in rats showed that the pharmacokinetics of the tricarbonyl core radiopharmaceutical (99m)Tc(CO)(3)-nitrilotriacetic acid, (99m)Tc(CO)(3)(NTA), were essentially identical to those of (131)I ortho-iodohippuran ((131)I-OIH), the clinical gold standard for the measurement of effective renal plasma flow. Our objective was to compare the pharmacokinetics of these 2 tracers in healthy volunteers. METHODS: (99m)Tc(CO)(3)(NTA) was prepared with commercially available NTA and a commercially available kit and isolated by reversed-phase high-performance liquid chromatography. Approximately 74 MBq (2 mCi) of (99m)Tc(CO)(3)(NTA) were coinjected with 9.25 MBq (250 microCi) of (131)I-OIH in 9 volunteers, and simultaneous imaging of each tracer was performed for 24 min. Plasma clearances were determined from 8 blood samples obtained 3-90 min after injection using the single-injection, 2-compartment model. Plasma protein binding, red cell uptake, and percentage injected dose in the urine at 30 and 180 min were determined. RESULTS: There was no difference in the plasma clearances of (99m)Tc(CO)(3)(NTA) and (131)I-OIH, 475 +/- 105 mL/min versus 472 +/- 108 mL/min, respectively. The plasma protein binding and red cell uptake of (99m)Tc(CO)(3)(NTA) were 43% +/- 5% and 9% +/- 6%, respectively; both values were significantly lower (P < 0.001) than the plasma protein binding (75% +/- 3%) and red cell uptake (17% +/- 5%) of (131)I-OIH. There was no significant difference in the percentage injected dose recovered in the urine at 30 min and at 3 h; for comparison, the percentage dose in the urine at 3 h was 91% +/- 4% for (99m)Tc(CO)(3)(NTA) and 91% +/- 6% for (131)I-OIH (P = 0.96). Image quality with (99m)Tc(CO)(3)(NTA) was excellent, and the renogram parameters were similar to those of (131)I-OIH. CONCLUSION: Preliminary results in healthy volunteers suggest that the pharmacokinetic behavior of (99m)Tc(CO)(3)(NTA) is comparable to that of (131)I-OIH.

99mTc-NC100692--a tracer for imaging vitronectin receptors associated with angiogenesis: a preclinical investigation.

INTRODUCTION: Technetium 99m (99mTc)-NC100692 is being developed as a marker of vitronectin receptor expression. The purpose of this study was to confirm the binding affinity [dissociation constant (Kd)] of 99mTc-NC100692 for a range of integrin receptors including alphavbeta3 and alphavbeta5 as well as to establish the biodistribution and metabolic stability of 99mTc-NC100692 in Wistar rats. METHODS: The Kd of 99mTc-NC100692 for a range of human integrin receptors was established in an in vitro saturation binding assay. The biodistribution and metabolic stability of 99mTc-NC100692 in normal Wistar rats was investigated. RESULTS: The Kd of 99mTc-NC100692 to alphavbeta3 and alphavbeta5 was less than 1 nM. It was not possible to saturate the binding of 99mTc-NC10092 towards alphaIIbbeta3, alpha5beta1, alpha3beta1 or alpha1beta1, and as a result, accurate Kd values could not be determined. The biodistribution of 99mTc-NC100692 in male and female Wistar rats showed that radioactivity was rapidly excreted, predominantly into the urine, with very little background tissue retention apart from the liver and kidneys. Kidney and liver retention was reduced in the presence of excess NC100692 ligand. In vivo, there was little systemic metabolism of 99mTc-NC100692. CONCLUSIONS: 99mTc-NC100692 has a high affinity for the vitronectin receptors that are associated with angiogenesis. 99mTc-NC100692 is metabolically stable in the systemic circulation of rats with a biodistribution that is favourable for imaging purposes. This evidence suggests that 99mTc-NC100692 might be a useful marker of vitronectin receptor expression in vivo.

Pharmacokinetics and normal scintigraphic appearance of 99mTc aprotinin.

OBJECTIVE: To confirm the pharmacokinetics and biodistribution of 99mTc aprotinin in normal volunteers and to determine the optimum time for scanning post-injection, prior to further investigations of 99mTc aprotinin as an imaging agent for amyloidosis. METHODS: Five patients (three men and two women, average age 49 years, age range 38-66 years) without a history of amyloidosis or any of the associated diseases, were included in this prospective study. Blood and urine were collected and images were performed of the whole body and wrists. CONCLUSIONS: Normal biodistribution of 99mTc aprotinin includes early cardiac and lung activity in the blood pool phase with subsequent hepatic activity and renal excretion with variable splenic activity. There is variable bowel uptake on later images. The best quality images were obtained 90 min post-intravenous administration, and this is likely to be the optimum time for clinical imaging.

A comparison of the biodistribution and biokinetics of (99m)Tc-anti-CD66 mAb BW 250/183 and (99m)Tc-anti-CD45 mAb YTH 24.5 with regard to suitability for myeloablative radioimmunotherapy.

Radioimmunotherapy (RIT) with radiolabelled monoclonal antibodies (mAbs) is an effective method of achieving myeloablation in leukaemia patients prior to stem cell transplantation (SCT). We wished to compare the approaches of specific binding to leukaemic blasts and non-specific binding to benign red marrow cells, which results in a myeloablative "cross-fire" effect. Therefore, we prospectively evaluated the biodistribution and biokinetics of the anti-CD45 mAb YTH 24.5 and the anti-CD66 mAb BW 250/183 with regard to their suitability for myeloablative RIT. The red marrow selective anti-CD66 mAb BW 250/183 (IgG1) binds to normal granulopoietic cells. In contrast, the anti-CD45 mAb YTH 24.5 (IgG2b) binds to 85-90% of acute leukaemic blasts and almost all haematopoietic white cells. Patients with leukaemic blast infiltration of the marrow <25% and assigned for RIT and SCT were included. Twelve patients (eight male, four female; median age 46+/-7 years) with AML (5), CML (5) or ALL (2) were examined. Both mAbs were labelled with technetium-99m. Within 48 h, 906+/-209 MBq (99m)Tc-anti-CD66 mAb and 760+/-331 MBq (99m)Tc-anti-CD45 mAb were injected consecutively. Scintigraphic and urinary measurements were performed 1, 2, 4 and 24 h after injection. Serum activities were evaluated 2, 5, 10, 15, 30 and 60 min and 2, 4 and 24 h after injection. Compared with the anti-CD45 mAb, the anti-CD66 mAb showed an approximately fourfold higher accumulation in the red marrow, a 2.5-fold lower accumulation in the liver and similar accumulation in the kidneys. The serum activity (% of the injected dose) initially decreased faster for the anti-CD45 mAb but was similar for the two mAbs 24 h after injection: 3.3%+/-1.2% (anti-CD66 mAb) and 2.4%+/-1.1% (anti-CD45 mAb). The cumulated urinary excretion was 17%+/-6.6% (anti-CD66 mAb) and 27.3%+/-7.9% (anti-CD45 mAb) 24 h after application. In these patients with low tumour load, the anti-CD66 mAb BW 250/183 showed more favourable properties in terms of biodistribution and pharmacokinetics. Thus, it appears superior to anti-CD45 mAb YTH 24.5 in selectively increasing the marrow dose and avoiding extramedullary organ toxicity.

New bone-seeking agent: animal study of Tc-99m-incadronate.

OBJECTIVE: Disodium cycloheptylaminomethylenediphosphonate monohydrate (incadronate disodium) is a third-generation bisphosphonate compound which potently inhibits bone resorption, and a highly effective drug in the treatment of metastatic bone disease. We first labeled incadronate disodium with 99mTc, and examined its biodistribution and bone uptake after intravenous injection in rats to assess its potential for clinical use as a bone-seeking agent for judgment of the therapeutic effect of incadronate on bone metastases. Bone scan with 99mTc-labeled incadronate (99mTc-incadronate) may yield important information prior to the use of incadronate for treatment of bone metastases. METHODS: Synthesis of 99mTc-incadronate was carried out by reduction of 99mTc-pertechnetate in the presence of SnCl2 and N2 gas. Normal rats were injected with 18.5 MBq (0.5 mCi) 99mTc-incadronate in a volume of 0.1 ml intravenously and then sacrificed at 15 min, 30 min, 1 h or 2 h (six rats at each time point) after injection. Samples of muscle, stomach, small intestine, kidney, liver and bone (femur) were taken and weighed. In addition, a 1-ml sample of blood was drawn from the heart, and urine was taken from the urinary bladder immediately after sacrifice. Samples were measured for radioactivity and expressed as percent uptake of injected dose per gram or per milliliter (% ID/g or ml). Bone-to-blood and bone-to-muscle uptake ratios were determined from the % ID/g or ml values for these organs. RESULTS: The greatest accumulation of 99mTc-incadronate was found in bone. Radioactivity in bone was as high as 3.22 +/- 0.68% ID/g at 2 hours after injection. Scintigraphic images of 99mTc-incadronate in normal rats revealed highly selective skeletal uptake. CONCLUSION: 99mTc-incadronate exhibited high uptake in bone, and relatively low uptake in soft tissue, suggesting that it may be useful as a bone-seeking agent for judgment of the therapeutic effect of incadronate on bone metastases, by determining the degree of its accumulation in metastatic bone lesions.

[Radiopharmacokinetic and gammagraphic studies for calculating personalized dosimetry]. / Estudios radiofarmacocinéticos y gammagráficos para cálculos de dosimetría personalizada.

In nuclear medicine radiation absorbed doses are important in the patient's risk/benefit evaluation and are estimated by means of biological and complex mathematical models. The biological model includes radiopharmacokinetic data obtained through blood and urine samples taken at given intervals. A useful mathematical model is the MIRD model and with the value for the time of residence tau the MIRDOSE3 computer program uses several anatomic models and calculates radiation absorbed dose for 25 organs. At the Radiopharmacy Unit of the Nuclear Medicine Department at INCMNSZ two new bone seeking radiopharmaceuticals, 99mTc-ABP and 188Re-ABP, have been designed, characterized and animal-tested. Radiopharmaceutical parameters and sequential scanning were obtained for diagnostic 99mTc-ABP in 10 normal subjects and the aim was to use % 24 hour urine elimination and % bone uptake to calculate radiation absorbed dose and extrapolate the values to 188Re-ABP as the basis for a therapeutic treatment. 99mTc-ABP was eliminated in women's urine 63.2 +/- 7.3%/activity and 70 +/- 11%/activity in men. In women 36.8 +/- 7.3% of the radiopharmaceutical remains on the bone surface and in men 30 +/- 11%. ROIs were drawn on the images and the time-integrated renal cpm/pixel/ROI gave a residence time tau = 0.52 h. Cumulative bone activity A calculated with A = 1.443 (T1/2) A0 was 2358 +/- 469 MBq h for women and 1923 +/- 707 MBq h for men. Residence time tau was 3.19 +/- 0.63 h in women and 2.6 +/- 0.95 h in men. Radiation absorbed dose for the whole body was 0.0020 +/- 0.0004 mGy/MBq for women and 0.0013 +/- 0.0005 mGy/MBq for men. For women's bone marrow it was 0.0063 +/- 0.0013 mGy/MBq and for men 0.0041 +/- 0.0015 mGy/MBq. 188Re-ABP behaves as 99mTc-ABP therefore, the effective dose given by 188Re, a beta emitter, would be for women 0.0936 mSv/MBq and for men 0.0608 mSv/MBq. These characteristics and the radionuclidic characteristics of 188Re indicate that 188Re-ABP might be a good bone metastases pain palliation radiopharmaceutical.

Biodistribution and renal excretion of isomers of the cationic tracer, (99m)Tc diaminocyclohexane (DACH): biodistribution of cationic renal tracers.

The buildup of organic anions in the plasma in the uremic state can competitively inhibit the tubular extraction of para-aminohippurate or (131)I ortho-iodohippurate (OIH) and lead to spuriously low measurements of effective renal plasma flow (ERPF). This problem can be circumvented by the use of cationic tracers. The cationic renal tracer, (99m)Tc labeled diaminocyclohexane ((99m)Tc DACH), has a clearance of 80% of OIH in mice but its clearance in humans is relatively low, only 30% of OIH. The (99m)Tc DACH isomer(s) used in prior studies, however, was not clearly defined and may have consisted of a single isomer or a combination of isomers. Since the anionic isomers of some (99m)Tc renal tracers have been shown to have widely different clearances, the biodistribution and urine excretion of the (99m)Tc cis-, trans-S,S, trans-R,R and +/-trans-DACH isomers were compared in Sprague-Dawley rats at 10 minutes and 60 minutes postinjection to determine if one of the (99m)Tc DACH isomers may be a significantly better renal tracer than the others. The red cell binding of (99m)Tc +/- trans-DACH was also determined. All of the isomers showed a high degree of specificity for the kidney with minimal secretion into the gastrointestinal tract. Urine excretion of the 4 tracers, however, was only 38-48% that of OIH at 10 minutes and 66-84% that of OIH at 60 minutes. Red cell binding was 6.9%. Cationic renal tracers have the potential to provide a more accurate measurement of ERPF than anionic tracers. Based on the animal data, however, it is unlikely that any of the (99m)Tc DACH isomers will have a substantially higher clearance in humans than the form of (99m)Tc DACH originally tested. Development of alternative cationic renal tracers is warranted.

Clearance and renal extraction of technetium-99m-L,L-ethylenedicysteine, I-131-ortho-iodohippurate and I-125-iothalamate in pigs.

99mTc-L,L-ethylenedicysteine (99mTc-EC) has been proposed as a 99mTc-labelled alternative to radio-iodinated ortho-iodohippurate (OIH) for renal imaging and evaluation of renal function. The kinetics of this new renal function agent were studied by a single-injection plasma clearance technique in pigs. 99mTc-EC, 131I-OIH and 125I-iothalamate were injected and the plasma concentration of the three tracers was followed for 240 min. Renal, hepatic and total plasma clearance were calculated. There was no difference between the renal plasma clearance of 99mTc-EC and 131I-OIH (175 +/- 9 versus 178 +/- 8 ml min-1, P = 0.43), whereas the difference between the total plasma clearance of 99mTc-EC and 131I-OIH was highly significant (268 +/- 16 versus 185 +/- 9 ml min-1, P = 0.0001). 99mTc-EC had a significant hepatic clearance of 83 +/- 10 ml min-1 whereas the hepatic clearance of 131I-OIH was negligible. Renal plasma extraction of both 99mTc-EC and 131I-OIH decreased significantly between 2 and 240 min post-injection from 0.85 to 0.45% for 99mTc-EC and from 0.93 to 0.57% for 131I-OIH. Red blood cell binding of 99mTc-EC and 131I-OIH was 6.1% and 20%, respectively. The protein binding of 99mTc-EC and 131I-OIH was 32% for both tracers. We conclude that 99mTc-EC is not a suitable tracer for measuring renal function by the single-injection plasma clearance technique in pigs. This is due to a decreasing renal extraction and a significant hepatic clearance.

99mTc-HMPAO as a tracer of cerebral blood flow in newborn infants.

Studies on the kinetics of 99mTc-D,L-hexamethylpropylene amine oxime (99mTc-HMPAO) in adults have shown that it is not an ideal tracer of CBF because it underestimates high-flow areas. Knowledge of the kinetics of the tracer is important in evaluating the studies. The kinetics of 99mTc-HMPAO in infants may be different from that in adults, therefore, we examined the cerebral uptake and retention of 99mTc-HMPAO in neonates and estimated the degree of brain-to-blood back diffusion by comparing corresponding 133Xe flow images and 99mTc-HMPAO distribution images. In addition, we measured the urinary excretion of 99mTc-HMPAO. Regional CBF was measured using a mobile brain-dedicated, fast-rotating, four-head multidetector system specially designed for neonatal studies. Tracers were 99mTc-HMPAO (4 MBq/kg) and 133Xe (500 MBq/kg). Cerebral uptake and leak-out of 99mTc-HMPAO were measured by a single scintillation crystal placed over the frontoparietal part of the infant's head. The cerebral retention of 99mTc-HMPAO was analyzed in 50 infants. The mean gestational age and birth weight (95% confidence interval) were 34.4 weeks (32.2-35.7) and 2,326 g (1,954-2,995), respectively. The cerebral uptake of 99mTc-HMPAO was examined in 16 of the 50 infants, and activity during 24 h was monitored in five. In 11 infants, corresponding 133Xe studies were performed. Urinary excretion was studied in 12 infants. The maximal activity in the brain was reached 90s after i.v. injection and was 104% (98-111) of the stable level, which was reached approximately 3 min after the injection. The decay corrected leakout of the tracer during the following 24 h was 1.0% (0.4-1.5) per hour. The cerebral retention was calculated at 6.8% (6.1-7.6), highest in the group of ictal studies and lowest in premature infants with intracranial hemorrhage. The mean value of the fixation/clearance ratio alpha was estimated at 3.4 (2.8-4.4). The mean urinary excretion over 24 h was 19.5% (11.4-27.7) and was significantly related to renal function as indicated by serum urea (p = 0.02 r2 = 0.55). A four-compartment model describing the kinetics of 99mTc-HMPAO is shown to be valid in neonates. The cerebral retention of the tracer is higher in neonates because of higher extraction and lower initial back diffusion from brain to blood. In linearizing 99mTc-HMPAO distribution images, a smaller correction is necessary, and we propose a value of the correction factor of 3.4. In this way, 99mTc-HMPAO is a more reliable tracer of the distribution of CBF in neonates compared with adults. The urinary excretion is significantly reduced compared with adults, and the radiation dose to the bladder wall is reduced. The effective dose is 0.3 mSv/MBq/kg.

Labelling, control and radiopharmacological evaluation of 99mTc-adenosine 5'-diphosphate (99mTc-ADP) as tumour seeking agent.

A study of 99mTc-adenosine-5'-diphosphate (99mTc-ADP) as a radiopharmaceutical for tumour diagnosis is presented. Two different labelling methods, using SnCl2 in alkaline solution and Zn as reducing agents, were developed. Reduction with Sn(II) alkaline solution was the selected method because a lower concentration of ADP (0.5 mg/mL) could be used and a higher radiochemical yield was achieved. A labelled molecule with a radiochemical purity higher than 95%, in vitro stability of at least 6 hours and an over all negative charge was obtained Biodistribution studies carried out in normal mice and rats revealed rapid urinary excretion and no specific accumulation of activity in any other particular organ. This behaviour was similar to that reported for 99mTc-adenosine-5'-triphosphate (99mTc-ATP). Rapid blood clearance, that could be fitted to a bicompartimental model, was also verified. No evidence of in vivo instability was observed. Studies in mice and rats bearing spontaneous mammary adenocarcinomas were performed and the results were compared to those from the 99mTc-ATP studies. Although the tumour models used were not the same, the incorporation of both labelled compounds was very similar. Radioactivity uptake in the tumour and the tumour-to-blood ratio were not notably high. However, a significant increment was observed in the tumour-to-muscle ratio (1.0 +/- 0.2 at 30 minutes to 2.7 +/- 0.4 at 240 minutes). Whole-body autoradiography enabled tumour visualization. Further investigations, including scintigraphic imaging, must be carried to complete the clinical evaluation of 99mTc-ADP as a tumour seeking agent.

Technetium-99m labelled hydrazinonicotinamido human non-specific polyclonal immunoglobulin G for detection of infectious foci: a comparison with two other technetium-labelled immunoglobulin preparations.

Recently a new linker - hydrazinonicotinate (HYNIC) - was introduced for labelling of proteins and peptides with technetium-99m. HYNIC and other linkers have been used for labelling of human non-specific polyclonal immunoglobulin G (hIgG) with 99mTc for the detection of infections. In this study we compared the tissue distribution of three different 99mTc-hIgG preparations in groups of five Wistar rats with a focal intramuscular infection with Staphylococcus aureus. We compared 99mTc-HYNIC-hIgG with 99mTc-hIgG labelled via the so-called Schwarz method (reduction of disulphide bonds) and with the 99mTc-labelled commercially available Technescan-HIG. Unlike the HYNIC linker, in the two other labelling methods free sulph-hydryl groups are involved in the binding of 99mTc. High-performance liquid chromatography analysis of the labelled preparations and of plasma samples revealed aggregate or polymer formation in all three agents; this was least pronounced in the product labelled by means of the Schwarz method. The tested preparations did not show signs of degradation in vitro. The difference in linker chemistry was reflected in the tissue distribution. Thus the biodistribution of 99mTc-HYNIC-hIgG was significantly different from the distribution of the two other preparations: abscess (1.4%+/-0.2%ID/g), muscle, liver, spleen, plasma, lung, bone marrow, and small intestine concentrations were higher at 24 h p.i.; kidney uptake (1.19%+/-0.08%ID/g) was significantly lower. The abscess-to-plasma and the abscess-to-muscle ratios (0.5 and 11, respectively), however, were in the same range for the three preparations tested. Quantitative analysis of the scintigraphs revealed that the total body clearance of 99mTc-HYNIC-hIgG was significantly slower than for the other agents. The abscess uptake of 99mTc-HYNIC-hIgG as a percentage of the remaining body activity was significantly higher. Based on its high abscess uptake, its low uptake in the kidneys and the high percentage of its abscess uptake in relation to the remaining body activity, we conclude that 99mTc-HYNIC-hIgG seems superior to the two other preparations tested for the detection of infections.

Detection of diffuse skeletal lesions by monitoring the kinetics of labeled phosphonate.

A method of detecting of diffuse skeletal involvement in patients with metastatic tumors or with metabolic diseases is presented. The study consisted of 31 patients without bone disease and of 26 selected patients with diffuse skeletal involvement. The kinetics of 99mTc-dicarboxypropane diphosphonate (DPD) were calculated by monitoring the plasma and urine concentrations up to 5 hours after administration. Using these data, the renal clearance as well as the increase in urinary excretion of 99mTc-DPD were determined. The results indicate that measurement of the quantity of 99mTc-DPD excreted in the urine after 3 hours allows a reliable separation of the patients with diffuse skeletal lesions from normals. Other calculations such as renal clearance as well as the drop in plasma concentration were less sensitive. The test may be performed simultaneously with bone scintigraphy without additional radiation burden to the patient.

Clinical evaluation of 99mTc diaminocyclohexane, a renal tubular agent with cationic transport: results in healthy human volunteers.

As alternatives to anionically transported hippuran, structure distribution experiments on a series of 99mTc-labelled primary substituted ethylene diamine compounds led to selection of 99mTc diaminocyclohexane (DACH) for clinical evaluation, 99mTc DACH, a cation with the structure trans-[O2(DACH)2 99mTc]+ is prepared by mixing 50 mumol DACH, 1 mumol stannous tartrate and 500 MBq of 99mTc. Seven normal volunteers underwent renal imaging and clearance studies using 150 MBq of 99mTc DACH and 1 MBq of 125I hippuran simultaneously. The images with 99mTc DACH revealed good uptake and excretion. The mean +/- 2 SD values of parenchymal and whole-kidney transit time indices and mean parenchymal transit time were 46 +/- 33, 75 +/- 64 and 141 +/- 51 s, respectively, similar to mercaptoacetyl triglycine. The mean clearance of 99mTc DACH was found to be 163 ml/min (SD = 32). Following cationic blockade with 900 mg oral thiamine, significant reduction (p < 0.001) in DACH clearance was noted, but hippuran clearance remained unaltered. The results support the hypothesis that 99mTc DACH is transported cationically.

Evaluation of the renal excretion characteristics of technetium-99m mercaptoacetylglycyl-D-alanylglycine in healthy volunteers.

During a study of C-methyl derivatives of technetium-99m mercaptoacetyltriglycine (99mTc-MAG3) it was found that the isomer of 99mTc-mercaptoacetylglycyl-D-alanylglycine (99m-TC-MAGAG-DA) is superior to 99mTc-MAG3 with regard to its renal excretion characteristics in both mice and the baboon. We have now compared the renal handling of 99mTc-MAGAG-DA and 99mTc-MAG3 in 6 healthy volunteers in a paired study. Renograms of 99mTc-MAGAG-DA show a shorter time to renal maximum and a lower residual renal activity at 30 min post-injection (p.i.). The urinary excretion of 99mTc-MAGAG-DA is higher at both 30 and 60 min p.i. The plasma concentration of 99mTc-MAGAG-DA is lower than that of 99mTc-MAG3 at each moment up to 60 min p.i., and the plasma clearance is accordingly higher. It is concluded that 99mTc-MAGAG-DA is excreted more efficiently than 99mTc-MAG3, but the preparation of 99mTc-MAGAG-DA requires a HPLC purification step, and this limits its practical clinical usefulness.

Quantitation of the hepatobiliary dynamics in clinically normal dogs by use of 99mTc-iminodiacetate excretory scintigraphy.

The hepatobiliary dynamics of a 99mTc-labeled derivative of iminodiacetate were investigated in 29 healthy dogs. A 2-compartment model proved to be adequate to describe the hepatic time-activity curve. Model-derived variables for the hepatic accumulation and the biliary excretion and transport were used as a reference for evaluation of a number of commonly used measurements directly derived from hepatic and biliary time-activity curves (graphic variables). The difference between t50(ex) and t95(ex), representing the moments when 50 and 95%, respectively, of the maximal count rate during the hepatic excretory phase were measured, proved to be an adequate graphic variable to quantitate biliary excretion. The use of other graphic variables to quantitate hepatobiliary functions seemed unjustified.