Blood metabolism of [methyl-11C]choline; implications for in vivo imaging with positron emission tomography

[methyl-11C]choline (11C-choline) is a radioligand potentially useful for oncological positron emission tomography (PET). As a first step towards the development of a kinetic model for quantification of 11C-choline uptake, blood metabolism of 11C-choline during PET imaging was studied in humans. High-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) were used for the analysis of 11C-choline and its radioactive metabolites. Prior to human PET imaging we studied ex vivo the biodistribution and metabolism of intravenously administered 11C-choline in rats. Our results revealed that the radioactivity accumulated particularly in kidney, lung, adrenal gland and liver. Chromatographic analysis showed that the level of unmetabolized 11C-choline in rat plasma decreased from 42% +/- 20% (mean +/- SD) at 5 min to 21% +/- 10% at 15 min after injection. In accordance with these findings, in humans the unmetabolized 11C-choline represents 62% +/- 19% of the total radioactivity in arterial plasma at 5 min after injection and 27% +/- 12% at 15 min. In human venous plasma the corresponding values were 85% +/- 12% and 48% +/- 12% at 5 and 10 min, respectively. The major metabolite observed in both human and rat plasma was identified as 11C-betaine. In human arterial plasma this maximally represented 82% +/- 9% of the total radioactivity at 25 min after radiotracer injection. By 20 min after injection, the 11C-choline and 11C-betaine in human arterial plasma reached a plateau, and their fractional activities remained nearly constant thereafter. Although most of the circulating 11C-choline in blood is transported to tissues, it does not disappear totally from blood within the first 40 min after tracer injection.     

In vitro evaluation of canine leukocytes radiolabeled in whole blood with (99m)Tc stannous colloid

INTRODUCTION: Technetium-99m stannous colloid ((99m)TcSnC)-labeled leukocytes are used to investigate a variety of inflammatory diseases in human medicine. The present study investigates the in vitro behavior of canine leukocytes labeled in whole blood with (99m)TcSnC. METHODS: Blood samples from 10 healthy dogs were labeled with (99m)TcSnC using a standard procedure. The distribution of radioactivity among blood components (plasma, leukocyte layers and erythrocytes) was measured following separation of the radiolabeled samples across Histopaque density gradients. Phagocytic function of labeled and unlabeled leukocytes was estimated using zymosan particles. Labeling retention by leukocytes was determined at 1, 3, 4 and 7 h postlabeling. RESULTS: The mean+/-standard error percentage of radioactivity associated with plasma, erythrocyte and leukocyte fractions was 2.0+/-0.21%, 55.5+/-0.60% and 42.5+/-0.54%, respectively (the last comprising 70.2+/-0.83% in polymorphonuclear leukocytes and 29.8+/-0.83% in mononuclear leukocytes). Labeled canine leukocytes had a phagocytic activity of 91.3+/-0.28% (control, 91.7+/-0.26%). The radiolabeled canine leukocytes retained 94.1+/-0.30% of radioactivity at 7 h postlabeling. CONCLUSIONS: Radiolabeling of canine leukocytes in whole blood with (99m)TcSnC has minor adverse effect on their phagocytic function. The radiolabeled canine leukocytes retained a large percentage of radioactivity for at least 7 h postlabeling.     

In vivo viability of 111In-labelled granulocytes demonstrated in a sham-dialysis model

In seven febrile patients undergoing regular dialysis treatment, sham-dialysis with a dialyzer equipped with a cuprophane membrane was performed during a routine 111In-oxine white blood cell scan with "pure" granulocytes isolated on a discontinuous gradient (Percoll/plasma: n = 5; Metrizamide/plasma: n = 2). The patients were in contact with the cuprophane membrane over 45 or 90 min. Twenty-five (+/- 5) minutes after the start of the dialysis, the peripheral leucocyte count (59 +/- 22%) and the 111In activity in the peripheral blood decreased to a minimum of their initial range (64 +/- 21%) because of leucocyte activation. The activity over both lungs increased symmetrically (29 +/- 15%), the spleen activity decreased (14.8 +/- 8%) and the liver activity remained constant. At the end of the dialysis (45-90 min post-injection), the number of circulating neutrophils, peripheral 111In activity and activity distribution in the organs regained their initial level. In conclusion, these data confirm previously described data concerning the sequestration of neutrophils into the lung during dialysis treatment. The data demonstrate the origin of the activated neutrophils in the circulation and the spleen. The identical behaviour of 111In-oxine-labelled and unlabelled granulocytes is demonstrated. Additionally, the accumulation of activity in the spleen is due not to opsonized cells but to sequestrated neutrophils, which are able to migrate from the spleen after adequate activation. The migration of activated cells into the lung explains the diagnostic difficulties posed by diffuse lung uptake in leucocyte scans in patients with leucocyte-activating diseases.     

Comparison of99mTc-tetrofosmin uptakes on planar images with those in excised rats organs with those in excised rats organs

The radioactivity in the organs adjacent to the heart causes interference with the quantitative assessment of myocardial uptake of tracer on scintigraphy. In order to investigate how much the functions of these organs affect myocardial uptake seen in imaging, we compared the myocardial uptake measured by means of a gamma camera with the actual activity in the excised organs. Methods: Thirty-three rats were imaged at 5, 10, 15, 30, 45, 60, 90 and 120 min after the administration of 99mTc-tetrofosmin, and % injected dose per pixel (%ID/pixel) for each organ was assessed on planar images (PI measurement). Percent injected dose per gram of tissue (%ID/g) in the heart as well as lungs, liver, gastrointestines and blood was measured by means of a well scintillation counter (WC measurement). Comparison between PI and WC measurements was performed with % uptake, the PI-to-WC ratio and heart-to-organ ratios. Results: Our WC measurement showed an increase in cardiac uptake until 30 min (1.67 +/- 0.31%) postinjection and subsequent gradual decrease, whereas PI measurement showed maximum activity of 1.81 +/- 0.52% at 15 min postinjection. There was a prominent difference between the two measurements, particularly at 10 min, with a PI/WC ratio of about 1.6 times. Our WC measurement showed maximum pulmonary uptake at 15 min (0.87 +/- 0.31%) and a gradual decrease over 15 min, whereas PI measurement showed maximum uptake at 10 min (1.14 +/- 0.38%). There was hardly any variation in activity observed later than at 10 min. Our WC measurement showed hardly any variance in hepatic activity from 5 min (0.77 +/- 0.19%) to 30 min (0.69 +/- 0.27%) with a subsequent gradual decrease. The percent uptake in PI measurement was generally greater than that in WC measurement, and high values were found at 10 min and 15 min with PI/WC ratios of about 3.3 times and 2.3 times, respectively. Conclusion: Percent uptakes in PI measurement were greater than those in WC measurement. The difference between the two measurements was prominent in the early phases. The cardiac uptake in PI measurement was significantly greater than that in WC measurement at 10 min. It was considered that this discrepancy between the two measurements was caused by the Compton scatter from the organs adjacent to the heart.     

114Inm oxine-labelled lymphocytes--therapeutic applications

It has shown that, after intravenous administration of autologous lymphocytes labelled with the beta-emitting radionuclide 114Inm, the cells initially migrate normally before succumbing to the toxic effects of the radiation. The radioactive material is then released from the cell and taken up by neighbouring radioresistant macrophages, thereby localizing a field of radiation to the site of lymphocyte death. Using this technique, lymphocytopoenia has been produced in rats. We have measured the whole-body distribution and excretion of radioactivity in patients who received escalating activities of 114Inm-labelled lymphocytes. All patients had active non-Hodgkin's lymphoma involving the spleen and liver which proved resistant to combination chemotherapy and conventional radiotherapy. Following intravenous administration, the labelled cells cleared rapidly from the vasculature with only 15% remaining in the peripheral blood at 30 min. The radioactivity continued to fall over the next 5 days to approximately 3% and was maintained at approximately 2% for up to 90 days. There was an almost immediate uptake of radioactivity by the spleen and liver which reached approximately 85% of the injected dose by 48 h. The localization of radioactivity stabilized by 48 h and thereafter the whole-body content fell by approximately 0.8% per day. Up to 5% of the administered radioactivity accumulated in the bone marrow. The activities administered were too low to produce a therapeutic response and no toxicity was experienced by the patients. A therapeutic study at higher activities is now underway.     

A phase I study of 99mTc-hR3 (DiaCIM), a humanized immunoconjugate directed towards the epidermal growth factor receptor

A phase I trial was conducted to evaluate the safety, tumour and normal tissue localization, pharmacokinetics and radiation dosimetry of Tc-hR3, a humanized monoclonal antibody directed towards the epidermal growth factor receptor, in 12 patients with recurrent or metastatic epithelial malignancies. Patients were injected intravenously with 3.0 mg or 6.0 mg (1010 MBq) of Tc-hR3. Blood and plasma concentrations of radioactivity were measured and a complete 24 h urine collection was obtained. Whole-body images were acquired up to 24 h post-injection and normal organ uptake quantified. Radiation dosimetry was estimated using MIRDose. Safety was evaluated by clinical observation, biochemical/haematological testing and by measuring immune response to Tc-hR3. There were no adverse effects, no changes in biochemical/haematological indices and no immune response to Tc-hR3. Tc-hR3 was rapidly cleared from the blood with a distribution half-life of 10.8+/-3.8 min. The volume of distribution, and clearance, were 180+/-37 ml.kg and 14+/-3 ml.kg.min, respectively. The elimination phase could not be discerned due to increasing blood radioactivity at later times. About 19-24% was excreted in the urine. Normal tissue uptake was mainly in the liver (44-50%), spleen (3-4%) and kidneys (3%). Imaging was positive in one patient with squamous cell carcinoma of the mouth and an involved cervical lymph node. The whole-body radiation dose from Tc-hR3 was 1.34+/-0.02x10 mSv.Bq. We conclude that Tc-hR3 exhibited an excellent safety profile. Future studies to determine the sensitivity and specificity of imaging with Tc-hR3 in a larger group of patients with pre-selection for epidermal growth factor receptor positivity are planned.     

Cell-dependent influence on the phagocytosis induced by non-ionic contrast medium injection

Iodinated contrast media (CM) can inhibit phagocytosis. To better understand the importance of this effect upon the elementary defence mechanism, the aim of the study was to compare the in vivo effect of non-ionic CM on the engulfing ability of peripheral blood phagocytic cells from patients undergoing CM-enhanced CT. Neutrophil granulocytes and monocytes from patients' peripheral blood obtained before and 30 min after CM injection were incubated with fluorescent-labelled Escherichia coli bacteria. Both the percentage of cells that engulfed bacteria and the phagocytic activity per cell has been determined by flow cytometry. We found that phagocytosis was greater in neutrophils than in monocytes. CM decreased the percentage of monocytes phagocyting bacteria, both at 4 degrees C (20.3%+/-3.3% versus 16.1%+/-2.0%; p<0.03) and at 37 degrees C (51.6%+/-4.1% versus 47.5%+/-2.6%; p>0.05), and increased the percentage of neutrophils at 4 degrees C (11.8%+/-2.1% versus 14.3%+/-2.2%; p<0.002) and at 37 degrees C (83.1%+/-3.6% versus 85.1%+/-3.2%; p>0.05). The phagocytic activity decreased significantly at 37 degrees C in monocytes (p<0.02), and was not affected in neutrophils. CM injection has different effects on both the percentage of phagocytosing cells and the phagocytic activity in monocytes and neutrophils. The inhibitory effect on monocyte phagocytosis seems to be compensated by neutrophils.     

Estimation by static SPECT of the radioactivity remaining after the first dose of two-fractionated 123I-IMP administration: the rate of increase in cerebral blood flow by ARG and the rate of increase in SPECT count

We devised a method for estimating the radioactivity remaining after the first dose of two-fractionated tracer administration in the acetazolamide activation study in a facility where static SPECT is used for 123I-IMP cerebral blood flow scintigraphy. Three static SPECT scans were obtained over 9-min periods beginning 10 min after the first 123I-IMP administration, to estimate the remaining activity until after 60 min. In 72 patients at rest, 9-min SPECT was performed 6 times, and 11 different patterns of distribution and the fitting coefficient were obtained. The correlation between the actual measurement and the estimation at the mid scan time of 59.5 min could be expressed as y = 1.0064x - 1.9656, and r = 0.9972 (p < 0.01). The correlation between the first and second measurements of cerebral blood flow in 5 patients given two-fractionated administration at rest could be expressed as y = 0.9919x + 0.2978, r = 0.9976 (p < 0.01), indicating the usefulness of this method for estimating the radioactivity remaining after the first dose. In 57 patients with unilateral cerebrovascular disease, the cerebral blood flow on the unaffected side increased by 55.4 +/- 13.1%, whereas the blood flow in 19 regions exhibiting severe stenosis on the affected side was increased only 1.4 +/- 10.5% (p < 0.01). In addition, the correlation between the rate of increase in cerebral blood flow and the rate of increase in SPECT count could be expressed as y = 0.8415x + 0.291, and r = 0.9979 (p < 0.01). Thus, with this method, the cerebral hemodynamic reserve test using the rate of increase in cerebral blood flow by the ARG method or the rate of increase in SPECT count can be completed within a day while maintaining the image quality of static SPECT.     

Radioimmunoimaging of experimental thrombi in dogs using technetium-99m-labeled monoclonal antibody fragments reactive with human platelets

Monoclonal antibody 50H.19, which reacts with human platelets, was converted to fragments, pretinned, and made into kits for subsequent radiolabeling with 99mTc. The antibody, which cross-reacts with dog platelets, was used to evaluate in vitro binding to blood clots and in vivo in experimental thrombi in dogs. After radiolabeling, 97.4 +/- 6.4% of the 99mTc was antibody-associated. The preparations retained immunoreactivity, as determined by: binding studies using whole blood and determining the ratio of cell-to-plasma radioactivity (ratios of 57.6-61.2) and binding of the antibody to clots (clot/serum ratios were 57.2-74.6%). Approximately 50% of the radioactivity was cleared from the blood in 3-6 min and 18-24% was excreted in urine within 3 hr. Experimental thrombi in dogs could be visualized consistently within 2-3 hr postinjection in peripheral veins and arteries, pulmonary arteries, and the right ventricle. In addition, damage to blood vessel intima without visible thrombi could also be detected. This method has the following advantages: short and simple pre-imaging preparation, and rapid visualization of thrombi with no need for blood-pool subtraction or delayed imaging.     

Increased inflammatory response of blood cells to repeated bout of endurance exercise

PURPOSE: The aim of the present study was to assess the effects of two 30-min consecutive exercise bouts on a treadmill at 80% VO2max separated by a 4-h rest interval, on blood cell counts and the production of tissue factor, cytokines, and eicosanoids in lipopolysaccharide (LPS)-stimulated blood. METHODS: Blood samples were taken from eight endurance athletes (mean+/-SD: age, 23.4+/-1.6 yr; VO2max, 66.0+/-6.4 L.min.kg), both immediately before and after each exercise bout. Cell counts were performed, and the heparinized blood was subjected to LPS-stimulation for 2 h. RESULTS: There was a significant rise in white blood cell counts after the first exercise bout (81%, P<0.001), increasing to 123% (P<0.001) after the second bout. After the first and second runs, the tissue factor activity in LPS-stimulated monocytes was enhanced by 70% (not significant) and almost 200% (P=0.012), respectively, compared with baseline values. The high monocyte responsiveness after the second bout remained undiminished 2 h later. Similarly, the interleukin (IL)-8 production had risen 70% (P=0.022) after the first run and 100% (P=0.005) after the second run, relative to baseline values. IL-6 or leukotriene B4 levels did not change significantly. The rise in LPS-induced thromboxane B2 was 80% (P=0.024) after the first run and 63% after the second run (P=0.071, not significant). VO2max correlated negatively with the concentration of granulocytes immediately after the second exercise bout (R=0.864, P=0.006). CONCLUSIONS: The results of this study are evidence that two physical exercise bouts separated by a 4-h rest are associated with an enhanced propensity of the blood cells to generate tissue factor activity and some proinflammatory products compared with one exercise bout.     

Mechanism of accumulation of 99mTc-sulesomab in inflammation.

99mTc-Sulesomab, the Fab fragment of anti-NCA-90, is used as an in vivo granulocyte labeling agent for imaging inflammation. It is not clear to what extent it targets cells that have already migrated into the interstitial space of an inflammatory lesion as opposed to circulating cells. The contribution to signal of radioprotein diffusion in the setting of increased vascular permeability is also poorly documented. METHODS: We compared the local kinetics of (99m)Tc-sulesomab and (99m)Tc-labeled human serum albumin (HSA), which have similar molecular sizes, in 7 patients with orthopedic infection proven by clearly positive (111)In-leukocyte scintigraphy. (99m)Tc-Sulesomab and (99m)Tc-HSA were administered in sequence separated by an interval of 2-6 d. Images were obtained 1, 3, 4, and 6 h after injection, and multiple venous blood samples were obtained for blood clearance measurement. Patlak-Rutland (P-R) analysis was performed to measure lesion and control tissue protein clearance. Target-to-background tissue (T/Bkg) ratios were calculated for each radioprotein and compared with the T/Bkg ratio for (111)In-leukocytes. (99m)Tc-Sulesomab binding to granulocytes was measured in vitro and ex vivo and to primed and activated granulocytes in vitro. RESULTS: After intravenous injection, <5% of the circulating radioactivity was cell bound with both radioproteins so that the P-R curves could therefore be assumed to represent extravascular uptake of free protein. The blood clearance (mean +/- SD) of sulesomab was 23.4 +/- 11.7 mL/min, approximately 5 times greater than that of HSA, for which it was 4.8 +/- 3.1 mL/min. Likewise, clearance into the lesion of sulesomab was consistently higher than that of HSA, on average about 3 times as high. Nevertheless, the T/Bkg ratios for sulesomab and HSA were similar, except at 6 h when that of HSA (2.14 +/- 0.6) was higher than that of sulesomab (1.93 +/- 0.5; P approximately 0.01). Both values were considerably less than the T/Bkg ratio on the (111)In-leukocyte images, which, at 22 h, was 12.3 +/- 5.3. Moderate clearance of sulesomab, but not HSA, was seen in the control tissue. Granulocytes bound significantly more (99m)Tc-sulesomab in vitro when primed or activated. CONCLUSION: (a) Sulesomab does not localize in inflammation as a result of binding to circulating granulocytes; (b) sulesomab is cleared into inflammation nonspecifically via increased vascular permeability; nevertheless, it may be cleared after local binding to primed granulocytes or bind to activated, migrated extravascular granulocytes; and (c) HSA produces a similar or higher T/Bkg ratio than sulesomab because sulesomab is cleared into normal tissues and because image positivity in inflammation is significantly dependent on local blood-pool expansion.     

Regional perfusion, oxygen metabolism, blood volume and immunoglobulin G accumulation at focal sites of infection in rabbits.

Infection causes remarkable changes in extracellular fluid volume, blood flow and oxygen consumption in the region of the lesion. To determine the sequence and magnitude of these changes, we performed serial scintigraphic measurements in 10 rabbits with experimental Escherichia coli abscesses. Positron emission tomography with C15O2, 15O2 and 11CO was used to measure regional blood flow, oxygen extraction (OEF) and blood volume; extracellular fluid volume was evaluated by single photon scintigraphy with indium-111 immunoglobulin G (IgG). Images were recorded following tracer administration at 1 and 7-10 days after infection. At the first imaging time, blood flow to infected muscle had increased by 40% compared with control sites (7.4 +/- 0.6 to 10.8 +/- 3.8 ml/min.100 g), OEF had decreased from 55% +/- 34% to 45% +/- 14%, and the infected-to-contralateral (I/C) ratio of IgG had increased to 3.34 +/- 1.85. At the later imaging time, flow had increased by almost threefold compared with day 1 (29.4 +/- 9.8 ml/min.100 g), OEF had decreased to 29% +/- 14%, and the I/C ratio for IgG had remained constant. Although OEF fell, oxygen delivery (OEF x flow) increased from 4.07 ml/min (control value) to 4.86 ml/min on day 1 and 8.64 ml/min on days 7-9. The infected-to-contralateral (IC) ratio of 15O2/C15O2 was 0.74 +/- 0.15 on day 1 and 0.77 +/- 0.10 at 7-9 days. These studies indicate that expansion of the extracellular fluid volume increases early in the evolution of the infection and exceeds changes in regional perfusion and oxygen delivery.     

Tumour uptake of radiolabelled pyrimidine bases and pyrimidine nucleosides in animal models. IX. Radiolabelled 1-(2'-fluoro-2'-deoxy-beta-D-ribofuranosyl)uracil and 1-(2'-chloro-2'-deoxy-beta-D-ribofuranosyl)uracil

The biodistribution of radiolabelled 1-(2'-fluoro-2'-deoxy-beta-D-ribofuranosyl)uracil (2'-FUdR) and 1-(2'-chloro-2'-deoxy-beta-D-ribofuranosyl)uracil (2'-ClUdR) was evaluated using in-vivo and in-vitro tumour models. 6-[3H]-2'-FUdR exhibited a maximum tumour:blood (T:B) ratio (Walker 256 carcinosarcoma) of 1.0 at 15 min after injection whereas 2-[14C]-2'-FUdR and 2'-[36Cl]-2'-ClUdR exhibited maximum T:B ratios (Lewis lung carcinoma) of 3.0 and 4.1 respectively at 120 min. Clearance of blood radioactivity after injection of 6-[3H]-2'-FUdR, 2-[14C]-2'-FUdR and 2'-[36Cl]-2'-ClUdR was rapid and best described by a biexponential function. The clearance half-lives of the short-lived components were calculated as 1.6 min (95.5%), 2.3 min (94.7%) and 1.2 min (96.0%) respectively. The clearance half-lives of the long-lived components were 23 h (4.5%) for 6-[3H]-2'-FUdR, 89 min (5.3%) for 2-[14C]-2'-FUdR, and 49 min (4.0%) for 2'-[36Cl]-2'-ClUdR. Less than 36% of the 14C radioactivity present in the urine 2 h after injection of 2-[14C]-2'-FUdR was associated with 2'-FUdR, whereas greater than 91% of the 36Cl radioactivity in the urine 2 h after injection of 2'-[36Cl]-2'-ClUdR was associated with 2'-ClUdR. Both 6-[3H]-2'-FUdR (less than 3.1 pmol/10(6) cells) and 6-[3H]-2'-ClUdR (1.0 +/- 0.2 pmol/10(6) cells) were incorporated into cultured Raji tumour cells in vitro to a lesser extent than the natural nucleosides uridine (137.2 +/- 3.8 pmol/10(6) cells) and 2'-deoxyuridine (23.5 +/- 2.5 pmol/10(6) cells) after a 20 min incubation.     

Factors influencing serial measurements of cardiac volumes by count-based methods: effects of elevated catecholamines, position, and exercise on technetium-99m-blood radioactivity concentration.

Most radionuclide methods for measuring cardiac volume require a determination of the blood radioactivity concentration. Thus, changes in blood radioactivity over time or during interventions might lead to spurious volume estimates unless blood radioactivity is serially measured. The effects of elevated epinephrine, posture and exercise on 99mTc-labeled blood radioactivity concentration were studied in 15 young (mean age = 28 yr) and 14 older (mean age = 68 yr) healthy males. An epinephrine infusion of 50 ng/kg/min resulted in a 4.1% +/- 1.0% increase in 99mTc-blood radioactivity (p less than or equal to 0.001) compared to baseline. Sitting increased blood radioactivity concentration by 12.3% +/- 3.0% (p less than 0.0002) compared to the supine position and peak supine bicycle exercise caused an 11.0% +/- 1.7% increase (p less than or equal to 0.0001) compared to supine rest. There was a significantly greater increase during peak supine exercise in the young compared to the older subjects (15.0% +/- 2.3% versus 6.3% +/- 2.0%, p less than or equal to 0.01). The mechanism of the increase in blood radioactivity concentration is uncertain, but presumably reflects the addition of hemoconcentrated red blood cells from the spleen and/or the loss of plasma volume. Failure to correct for the increased blood radioactivity concentration during exercise or pharmacological interventions will result in a significant error in serial measurements of cardiac volumes by methods requiring RBC radioactivity measurements.     

Intracavitary use of two radiolabeled tumor-associated monoclonal antibodies

Six patients with metastatic breast cancer and malignant pleural effusions and 13 patients with known or suspected ovarian cancer, underwent immunoscintigraphy after intracavitary (intrapleural or intraperitoneal) administration of iodine-131-(131I) or indium-111-(111In) labeled tumor associated monoclonal antibodies HMFG2 and H17E2. This method proved to be sensitive and specific with a true-positive result in 13 out of 14 patients with tumor and a true-negative result in five out of five patients without tumor. At any one time, 65%-80% of the whole-body radioactivity was closely associated with the cavity into which the radiolabeled antibody was administered while the radioactivity in the blood was always low, (approximately 4 X 10(-3) of administered dose/ml of blood). Concentrations of radiolabeled antibody (per gram of tumor tissue) ranged from 0.02%-0.1% of the injected dose in intracavitary tumors, but only 0.002% in a retroperitoneal metastasis. The specificity of this approach was documented in four control patients with benign ovarian cysts and in two patients who were imaged using both specific and nonspecific radiolabeled antibody. We conclude that the intracavitary administration of 131I- or 111In-labeled HMFG2 and H17E2 is a favorable route of administration and offers significant advantages over previously reported intravenous administration for the localization of breast or ovarian metastases confined to the pleural or peritoneal cavities.     

Estimation and optimization of the use of standard arterial input function for split-dose administration of N-isopropyl-p[123I]iodoamphetamine

Use of a standard arterial input function and calibrating it by a single blood sample or a continuous arterial blood sample has been researched for a repeat CBF assessment with split-dose administration of N-isopropyl-p[123I]iodoamphetamine (IMP). METHODS: The study population consisted of 5 normal volunteers and 5 patients with cerebrovascular disease. IMP was injected twice (111 MBq/2 ml each) into the anti-cubital vein at a constant infusion speed for 1 min. The arterial input function was monitored during the study including a continuous measurement of radioactivity concentration of both the whole-blood and the octanol-soluble component (Real-Input Function, RIF). Standard input function was determined, and was calibrated either by a single blood sample or a continuous blood sample to estimate the Estimated-Input Function (EIF). Area-Under-the Curve (AUC) was then compared between RIF and EIF. RESULTS: In case EIF was estimated with a single blood sample, the minimum error of estimated AUC was obtained when calibrated at 7 minutes after either the 1st or 2nd injections. Deviation of AUC for [0, 30] was +/- 6.6%, and +/- 5.0%, respectively. If calibrated with a continuous blood sample, the minimum error of AUC with the continuous blood sampling period of 10 min for [0, 30] and [30, 60] was +/- 5.3% and +/- 4.0%, respectively. CONCLUSIONS: AUC of EIF with either a single or continuous blood sampling appeared to have reasonably small errors, suggesting the validity of the use of standardized input function in the split-dose IMP SPECT.     

Pharmacokinetic studies of DISIDA disposition. I. Animal studies

The whole blood pharmacokinetics of intravenously administered 99mTc-disofenin (DISIDA) have been studied in dogs. Serial blood sampling permitted calculation of whole blood disposition rates, which principally represent liver clearance. There were striking differences in these rates between 6 normals and 7 animals in whom liver damage was induced by chronic bile duct ligation (256 vs 58 ml/min, P less than 0.001). Blood levels of radioactivity fell in a biexponential fashion characterized by rapid and slow disposition phases, whose half times were 2.4 and 58 min in normal animals. On 3 occasions, plasma was obtained from 1 animal by exsanguination 35 min after the administration of DISIDA and rapidly transfused into a 2nd animal. The whole blood pharmacokinetics of the second (recipient) animal showed a predominance of the slow disposition phase and a small rapid phase. The hepatic extraction ratio of blood radioactivity was measured in 3 dogs and was high (75%-90%) early after injection of DISIDA, but fell rapidly to remain around 10%. These experiments suggest the presence of two different species in the radiopharmaceutical studied, each being removed from the blood stream by the liver, but at different rates. The contribution of renal clearance to overall whole blood pharmacokinetics was negligible, since three nephrectomized dogs displayed similar pharmacokinetics to normals. Whole blood DISIDA pharmacokinetics are more complex than previously thought but appear to be capable of providing an accurate measure of liver function.     

Biodistribution, pharmacokinetics and imaging of (188)Re-BMEDA-labeled pegylated liposomes after intraperitoneal injection in a C26 colon carcinoma ascites mouse model

Nanoliposomes are important carriers capable of packaging drugs for various delivery applications through passive targeting tumor sites by enhanced permeability and retention effect. Radiolabeled liposomes have potential applications in radiotherapy and diagnostic imaging. The purpose of this study was to investigate the biodistribution, pharmacokinetics and imaging of nanotargeted (188)Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (RBLPL) and unencapsulated (188)Re-BMEDA after intraperitoneal (ip) injection in a C26 colon carcinoma ascites mouse model. The nanopegylated liposomes were labeled with (188)Re-BMEDA. The labeling efficiency of RBLPL was 82.3+/-4.5%. In vitro stability of RBLPL in normal saline at room temperature and in rat plasma at 37 degrees C for 72 h was 92.01+/-1.31% and 82.4+/-1.64%, respectively. The biodistribution studies indicated that the radioactivity in ascites was 69.96+/-14.08 percentage injected dose per gram (% ID/g) at 1h to 5.99+/-1.97% ID/g at 48 h after ip administration of RBLPL. The levels of radioactivity in tumor were progressive accumulation to a maximum of 6.57+/-1.7% ID/g at 24 h. The radioactivity of (188)Re-BMEDA in ascites reached the maximum level of 54.89+/-5.91% ID/g at 1 h and declined rapidly with time. Pharmacokinetic studies revealed that the terminal half-life, total body clearance and area under the curve of RBLPL were 5.3-, 9.5- and 9.4-fold higher than that of (188)Re-BMEDA in blood, respectively. These results suggested that the long circulation, bioavailability and localization of RBLPL in tumor and ascites sites, which also demonstrate that the ip administration of RBLPL is a potential multifunctional nanoradiotherapeutics and imaging agents on a C26 colon carcinoma ascites mouse model.     

Effect of edetate calcium disodium on yttrium-90 activity in bone of mice

The kinetics of Yttrium-90 (Y-90) in bone of mice was investigated in combination with edetate calcium disodium (CaNa2EDTA). One group of mice were intraperitoneally administered 37.5 mg/kg CaNa2EDTA or 0.9% NaCl as a control at 1, 22, 34, 46, 58, 70, 82, 94, 154 and 166 h after injection of Y-90 acetate (post-administration), and the biodistribution was studied at 3, 24, 72, 120 and 168 h postinjection of Y-90 acetate. No difference between the post-CaNa2EDTA-treated mice and the control was demonstrated in the radioactivity in the bone. A decrease in radioactivity in the liver and kidneys was accelerated, and the radioactivity was lower than the control at 120 h postinjection. The other group of mice were also given the same dose of chelator at 12 h and 1 h preinjection of Y-90 acetate and at 1, 22, 34, 46, 58, 70, 82, 94, 154 and 166 h after injection of Y-90 acetate (pre- and post-administration), the radioactivity in bone at 3 h postinjection was significantly lower than in the control (24.4 +/- 3.92% ID/g vs. 31.7 +/- 2.26% ID/g, p < 0.05), but the decrease was not sequential. A significant reduction in radioactivity in the blood, kidneys and liver was demonstrated at 3 h, 72 h and 72 h postinjection. In conclusion, the CaNa2EDTA with the administration schedule employed here cannot chelate the Y-90 from bone but the free Y-90 before deposition into bone.     

Myocardial extraction of teboroxime: effects of teboroxime interaction with blood.

The isolated perfused rat heart preparation was used to determine whether the interaction of blood with either 99mTc-teboroxime, 99mTc-sestamibi or 201TI affects the extraction of these myocardial perfusion agents. Hearts were retrogradely perfused at 72 cm H2O with Krebs-Henseleit buffer equilibrated with O2:CO2 (95:5). The hearts were paced at 5 Hz. Single-pass extraction of 99mTc-teboroxime (96% +/- 1%) was greater than that of 99mTc-sestamibi (15% +/- 1%) or 201TI (30% +/- 5%). Extraction of the hydroxide form of 99mTc-teboroxime was only 43% +/- 4%. When arterial blood obtained from rats administered 99mTc-teboroxime was injected into the perfused heart, extraction of 99mTc-teboroxime decreased progressively as its time in circulation was lengthened. Similar experiments using either 99mTc-sestamibi or 201TI showed that extraction of these agents was neither affected by the presence of blood nor residence in circulation. For 99mTc-teboroxime, extraction was 99.5% +/- 0.5%, 57% +/- 13%, 20% +/- 2% at 1, 5, and 60 min postinjection, respectively. In separate experiments, HPLC analysis of blood at 5, 15 and 60 min postinjection indicated that only 34% +/- 4%, 13% +/- 2%, and 2% +/- 1%, respectively, of the total 99mTc-teboroxime was free and was associated with extraction values of 44% +/- 7%, 28% +/- 5%, and 19% +/- 3%, respectively. The percentage of this free radioactivity that converted from the chloro to the hydroxide form was 9% +/- 2%, 6% +/- 2%, and 2% +/- 1%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)