Biodistribution and radiation dosimetry of [<Superscript>123</Superscript>I]ADAM in healthy human subjects: preliminary results

[(123)I]ADAM [2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM)] has recently been shown to be a very promising imaging ligand for the detection of serotonin transporters (SERT) in human brain, because of its high specificity for SERT. [(123)I]ADAM has previously been used only for animal studies. In this work, we investigated the radiation dosimetry and biodistribution of [(123)I]ADAM based on whole-body scans in healthy human volunteers. Following the administration of 196+/-20 MBq (range 157-220 MBq) [(123)I]ADAM, serial whole-body images were performed up to 24 h. Estimates of radiation absorbed dose were calculated using the MIRDOSE 3.0 program with a dynamic bladder model. Twelve source organs were considered in estimating absorbed radiation doses for organs of the body. The highest absorbed organ doses were found to the lower large intestine wall (8.3.10(-2) mGy/MBq), kidneys (5.2.10(-2) mGy/MBq), urinary bladder wall (4.9.10(-2) mGy/MBq) and thyroid (4.3.10(-2) mGy/MBq). The effective dose was estimated to be 2.2.10(-2) mSv/MBq. The results suggest that [(123)I]ADAM is of potential value as a tracer for single-photon emission tomography imaging of serotonin receptors in humans, with acceptable dosimetry and high brain uptake.     

Biodistribution and internal dosimetry of the 188Re-labelled humanized monoclonal antibody anti-epidemal growth factor receptor, nimotuzumab, in the locoregional treatment of malignant gliomas

OBJECTIVE: To evaluate the biodistribution, internal radiation dosimetry and safety of the 188Re-labelled humanized monoclonal antibody nimotuzumab in the locoregional treatment of malignant gliomas. METHODS: Single doses of 370 or 555 MBq of 188Re-labelled nimotuzumab were locoregionally administered to nine patients with recurrent high-grade gliomas, according to an approved dose-escalation study. SPECT, planar scintigraphy and magnetic resonance images were combined for dosimetric and pharmacokinetic studies. Blood and urine samples were collected to evaluate clinical laboratory parameters and for absorbed doses calculations. Biodistribution, internal dosimetry, human anti-mouse antibody response and toxicity were evaluated and reported. RESULTS: The 188Re-nimotuzumab showed a high retention in the surgically created resection cavity with a mean value of 85.5+/-10.3%ID 1 h post-injection. It produced mean absorbed doses in the tumour region of approximately 24.1+/-2.9 Gy in group I (patients receiving 370 MBq) and 31.1+/-6.4 Gy in group II (patients receiving 555 MBq); the normal organs receiving the highest absorbed doses were the kidneys, liver and urinary bladder. About 6.2+/-0.8%ID was excreted by the urinary pathway. The maximum tolerated dose was 370 MBq because two patients showed severe adverse effects after they received 555 MBq of 188Re-nimotuzumab. No patient developed human anti-mouse antibody response. CONCLUSIONS: A locoregional single dose of 188Re-labelled nimotuzumab of approximately 370 MBq could be used safely in the routine treatment of patients suffering with high-grade gliomas. The efficacy of this therapy needs to be evaluated in a phase II clinical trial.     

Biodistribution and planar gamma camera imaging of (123)I- and (131)I-labeled F(ab')(2) and Fab fragments of monoclonal antibody 14C5 in nude mice bearing an A549 lung tumor

Detection of antigen 14C5, involved in substrate adhesion and highly expressed on the membrane of many carcinomas, including lung cancer, provides important diagnostic information that can influence patient management. The aim of this study was to evaluate the biodistribution and planar gamma camera imaging characteristics of radioiodinated F(ab')(2) and Fab fragments of monoclonal antibody (mAb) 14C5 in tumor-bearing mice. METHODS: F(ab')(2) and Fab 14C5 fragments were radioiodinated using the Iodo-Gen method. In vitro stability, binding specificity and affinity of (125)I-labeled 14C5 fragments were studied in A549 lung carcinoma cells. Biodistribution, blood clearance and tumor-targeting characteristics of (131)I-labeled 14C5 fragments and intact mAb 14C5 were studied in Swiss nu/nu mice bearing A549 lung carcinoma tumors. Planar gamma imaging illustrated the potential use of these (123)I-labeled 14C5 fragments for radioimmunodetection (RID). RESULTS: Saturation binding experiments showed highest affinity for (125)I-labeled F(ab')(2) fragments (K(d)=0.37+/-0.10 nmol/L) and lowest affinity for (125)I-labeled Fab fragments (K(d)=2.25+/-0.44 nmol/L). Blood clearance studies showed that the alpha half-life (t(1/2)alpha) value for Fab, F(ab')(2) and mAb 14C5 was 14.9, 21 and 118 min, respectively. The beta half-life t(1/2)beta value for Fab, F(ab')(2) and mAb 14C5 was 439, 627 and 4067 min, respectively. (131)I-Fab fragments showed highest tumor uptake 3 h after injection (2.4+/-0.8 %ID/g), (131)I-labeled F(ab')(2) showed highest tumor uptake 6 h after injection (4.7+/-0.7 %ID/g) and for (131)I-labeled mAb highest tumor uptake was observed at 24 h (10.7+/-2.3 %ID/g). In planar gamma imaging, both labeled fragments gave better tumor-to-background contrast than (123)I-mAb 14C5. CONCLUSION: Fab and F(ab')(2) fragments derived from intact mAb 14C5 have significant potential for diagnostic and therapeutic applications and may provide new tools in mAb-based radiopharmaceuticals for targeting non-small cell lung cancer.     

Radiation dosimetry of a 99mTc-labeled IgM murine antibody to CD15 antigens on human granulocytes.

99mTc-labeled anti-stage specific embryonic antigen-1 (anti-SSEA-1) is an injectable IgM antibody derived from mice. It binds to CD15 antigens on some granulocytic subpopulations of human white blood cells in vivo after systemic administration. The purpose of this study was to measure biodistribution of 99mTc-labeled anti-SSEA-1 and perform radiation dosimetry in 10 healthy human volunteers. METHODS: Transmission scans and whole-body images were acquired sequentially on a dual-head camera for 32 h after the intravenous administration of about 370 MBq (10.0 mCi) of the radiopharmaceutical. Renal excretion fractions were measured from 10 to 14 discrete urine specimens voided over 27.9 +/- 2.0 h. Multiexponential functions were fit iteratively to the time-activity curves for 17 regions of interest using a nonlinear least squares regression algorithm. The curves were integrated numerically to yield source organ residence times. Gender-specific radiation doses were then estimated individually for each subject, using the MIRD technique, before any results were averaged. RESULTS: Quantification showed that the kidneys excreted 39.5% +/- 6.5% of the administered dose during the first 24 h after administration. Image analysis showed that 10%-14% of the radioactivity went to the spleen, while more than 40% went to the liver. Residence times were longest in the liver (3.37 h), followed by the bone marrow (1.09 h), kidneys (0.84 h) and the spleen (0.65 h). The dose-limiting organ in both men and women was the spleen, which received an average of 0.062 mGy/MBq (0.23 rad/mCi, range 0.08-0.30 rad/mCi), followed by the kidneys (0.051 mGy/MBq), liver (0.048 mGy/MBq) and urinary bladder (0.032 mGy/MBq). The effective dose equivalent was 0.018 mSv/MBq (0.068 rem/mCi). CONCLUSION: The findings suggest that the radiation dosimetry profile for this new infection imaging agent is highly favorable.     

Safety, biodistribution, and dosimetry of 123I-IMPY: a novel amyloid plaque-imaging agent for the diagnosis of Alzheimer's disease.

(123)I-IMPY (6-iodo-2-(4'-dimethylamino-)phenyl-imidazo[1,2-a]pyridine) is a novel radiopharmaceutical that selectively binds to Alzheimer's disease (AD) amyloid plaques. As a first step toward validating this radiopharmaceutical as an imaging biomarker for AD, we measured the whole-body biokinetics and radiation dosimetry of (123)I-IMPY in AD patients and cognitively normal control subjects. The pharmacologic safety profile of the compound was simultaneously assessed. METHODS: The sample included 9 subjects ranging in age from 44 to 80 y. Whole-body images were obtained for each subject (mean +/- SD, 9.0 +/- 3.2 scans per subject) for up to 48 h after the intravenous administration of 185 MBq (5 mCi) of (123)I-IMPY. The fraction of administered activity in 12 regions of interest was quantified from the attenuation-corrected geometric mean counts in conjugate views. Multiexponential functions were iteratively fit to each time-activity curve using a nonlinear, least-squares regression algorithm. These curves were numerically integrated to yield cumulated activity values for source organs. Radiation doses were then estimated with the MIRD technique. RESULTS: The radiotracer had no pharmacologic effects (produced no changes in heart rate, blood pressure, or laboratory results) on any of the subjects. Radiation dosimetry estimates indicated that the dose-limiting organ was the gallbladder, which received an average of 0.135 mGy/MBq (range, 0.075-0.198 mGy/MBq). The effective dose equivalent and effective dose for (123)I-IMPY were 0.042 +/- 0.003 mSv/MBq and 0.035 +/- 0.001 mSv/MBq, respectively. The mean effective dose for (123)I-IMPY was similar to that for (111)In-diethylenetriaminepentaacetic acid (0.035 mGy/MBq), less than half that for (111)In-pentetreotide (0.81 mGy/MBq), and approximately twice that for (123)I-IMP (0.018 mGy/MBq). No significant differences were found between men and women or between AD patients and control subjects. CONCLUSION: (123)I-IMPY may be a safe radiotracer with appropriate biokinetics for imaging amyloid plaques in AD patients.     

Dosimetry estimations for 123I-IAZA in healthy volunteers.

123I-Labeled iodoazomycin arabinoside (IAZA) is a marker of hypoxia in vivo. It has been used clinically to image hypoxic tissue in solid tumors, peripheral vascular disease of diabetic origin, blunt brain trauma, and rheumatoid joints and in an animal model of cerebrovascular disease. The radiation dose biodistribution for 123I-IAZA was studied to assess and characterize its suitability as a clinical radiopharmaceutical. METHODS: Six healthy volunteers each received a nominal 185-MBq (5 mCi) dose of 123I-IAZA administered as a slow (1-3 min) intravenous injection in the arm. Anterior and posterior whole-body planar images were acquired for each volunteer beginning immediately after injection and at 1-2, 3-4, 6-8, and 20-24 h after injection. Venous blood samples (0 h predose through 28 h after dosing) and 28-h cumulative urine samples were taken from each volunteer for pharmacokinetic analysis. Radiation dose estimates were performed for all volunteers, with "reference adult" (for men) and "adult female" (for women) phantoms, and both the International Commission on Radiological Protection 30 gastrointestinal tract model and the dynamic bladder model, using the MIRDOSE3 program. Two sets of estimates, 1 using a pharmacokinetic analysis of total serum radioactivity and 1 based on scintigraphic image data, were obtained for each volunteer after 123I-IAZA administration. RESULTS: Two compartments were discernible by pharmacokinetic analysis, and 4 compartments were discernible by image analysis. The urinary bladder wall received the greatest radiation dose (6.3E-02 +/- 8.7E-03 mGy/MBq), followed by the upper large intestinal wall (5.6E-02 +/- 1.2E-02 mGy/MBq), the lower large intestinal wall (5.0E-02 +/- 1.2E-02 mGy/MBq), and the thyroid (4.4E-02 +/- 1.4E-02 mGy/MBq). Approximately 90% of physiologically eliminated radioactivity was excreted through the kidneys. Radioactivity entering the intestinal tract from the gallbladder constituted <10% of biologically eliminated activity. CONCLUSION: The dosimetric analysis of 123I-IAZA in 6 healthy volunteers indicated that both disposition kinetics and radiation dosimetry support its clinical use for imaging tissue hypoxia.     

Phase I/II clinical trial of the humanized anti-EGF-r monoclonal antibody h-R3 labelled with 99mTc in patients with tumour of epithelial origin

AIM: To evaluate the biodistribution, internal radiation dosimetry and toxicity of the humanized MAb h-R3 labelled with Tc in humans. METHODS: Twenty-five patients with suspected epithelial-derived tumours were included in this study and divided into two groups: group I consisted of 10 patients who received 3 mg/1110 MBq (3 mg/30 mCi); and group II consisted of 15 patients who received 6 mg/2220 MBq (6 mg/60 mCi). Single photon emission computed tomography (SPECT) and planar images, and multiple blood and urine samples were collected up to 24 h after injection. Haematological parameters and adverse effects were classified according to the WHO criteria. Biodistribution, human anti-mouse antibody (HAMA) response and absorbed doses were estimated and reported. RESULTS: Liver, spleen, kidneys and heart were identified as source organs. Their higher uptakes were 53.3+/-6.4%ID, 2.0+/-1.4%ID, 9.8+/-4.3%ID and 2.8+/-0.9%ID, respectively. The urinary bladder and large intestine also had a significant uptake. The mean urinary excretion was around 22%ID. The liver received the highest absorbed doses followed by the kidneys and the urinary bladder wall. There were no haematological or biochemical abnormalities with clinical significance related to the product. No patient developed HAMA response. Preliminary analysis of clinical results showed a sensitivity of 76.5% and a specificity of 100%. CONCLUSIONS: The results of this study suggest that Tc-h-R3 could be used in patients in a safe and effective way, for the diagnosis of epithelial-derived tumours at the two evaluated dose levels.     

Radiation dosimetry estimates of [18F]-fluoroacetate based on biodistribution data of rats

We estimated the dosimetry of [(18)F]fluoroacetate (FAC) with the method established by MIRD based on biodistribution data of rats. We selected some important organs and computed their residence time, their absorbed doses and effective dose with the (%ID(Organ)) (human) data using OLINDA/EXM 1.1 program. We observed the highest absorbed doses in the heart wall (0.025mGy/MBq) and the lowest in skin (0.0079mGy/MBq). The total mean absorbed doses and the effective doses were 0.011mGy/MBq and 0.014mSv/MBq, respectively. A 370-MBq injection of FAC leads to an estimated effective dose of 5.2mSv. The potential radiation risk associated with FAC/PET imaging is well within the accepted limits.     

Biodistribution, dosimetry and metabolism of 11beta-methoxy-(17alpha,20E/Z)-[123I]iodovinylestradiol in healthy women and breast cancer patients.

The biodistribution and dosimetry of the 20E and 20Z stereoisomers of 11 beta-methoxy-(17alpha,20)-[123I]iodovinylestradiol (MIVE) were evaluated in six healthy women. Tumor uptake and metabolism of the 20Z isomer were evaluated in 13 women referred after abnormal mammography or after discovery of a suspect mass at physical examination. METHODS: The radiopharmaceuticals were prepared from their corresponding stannyl intermediates and administrated intravenously. Blood samples were drawn at different time intervals and urine was collected for up to 24 h. Metabolites were detected by radiochromatography. Tissue distribution was followed for up to 24 h by scintigraphic imaging. The dosimetry was computed according to the Medical Internal Radiation Dose scheme. RESULTS: The 20E and 20Z isomers exhibit similar biodistribution and dosimetry patterns. Chromatographic analysis of plasma samples of healthy volunteers and cancer patients, as well as in vitro plasma incubations, confirmed the in vivo stability of (20Z)-[123I]MIVE. Radioactivity was rapidly cleared from the blood by the liver and excreted through the gut, which received the highest radiation dose (0.211 mGy/MBq). The effective doses for the adult female and male phantom were 0.054 and 0.046 mSv/MBq, respectively. Among the 13 patients imaged with (20Z)-[123I]MIVE, 3 had fibrocystic disease with no focal uptake, 8 had good agreement with in vitro estrogen receptor determination and 2 were false-positive. CONCLUSION: The radiation dose after intravenous administration of 20E- or (20Z)-[123I]MIVE at imaging dose levels is within acceptable limits. There was a good correlation between uptake of (20Z)-[123I]MIVE and the presence of estrogen receptors in breast cancer patients.     

Human biodistribution and dosimetry of [123I]FP-CIT: a potent radioligand for imaging of dopamine transporters

This study reports on the biodistribution and radiation dosimetry of iodine-123-labelled N-ω-(flu- oropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)tropane ([¹²³I]FP-CIT), a promising radioligand for the imaging of dopamine transporters. In 12 healthy volunteers, conjugate whole-body scans were performed up to 48 h following intravenous injection of approximately 100 MBq [¹²³I]FP-CIT. Attenuation correction was performed using a transmission whole-body scan obtained prior to injection of the radioligand, employing a ¹²³I flood source. Blood samples were taken and urine was freely collected up to 48 h after injection of the radiotracer. For each subject, the percentage of injected activity measured in regions of interest over brain, striatum, lungs and liver were fitted to a multicompartmental model to give time-activity curves. The cumulative urine activity curve was used to model the urinary excretion rate and, indirectly, to predict faecal excretion. Using the MIRD method, nine source organs were considered in estimating absorbed radiation doses for organs of the body. The images showed rapid lung uptake and hepatobiliary excretion. Diffuse uptake and retention of activity was seen in the brain, especially in the striatum. At 48 h following the injection of [¹²³I]FP-CIT, mean measured urine excretion was 60%±9% (SD), and mean predicted excretion in faeces was 14%±1%. In general, the striatum received the highest absorbed dose (average 0.23 mGy/MBq), followed by the urinary bladder wall (average 0.054 mGy/MBq) and lungs (average 0.043 mGy/MBq). The average effective dose equivalent of [¹²³I]FP-CIT was estimated to be 0.024 mSv/MBq. The amount of [¹²³I]FP-CIT required for adequate dopamine transporter imaging results in an acceptable effective dose equivalent to the patient. Received 14 July and in revised form 26 September 1997     

Dosimetry of the dopamine transporter radioligand 18F-FPCIT in human subjects.

This study was designed to evaluate the radiation dosimetry in human subjects for a new radiopharmaceutical, N-(3-(18)F-fluoropropyl)-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane ((18)F-FPCIT). The goal was to determine a limiting dose consistent with accepted guidelines for use in clinical studies and to compare the radiation burden with other agents such as (123)I-FPCIT, (18)F-fluorodopa, and (18)F-FDG. METHODS: Dynamic PET scans of the urinary bladder were obtained in 6 subjects; 2 subjects had brain scans and 5 subjects had scans of the thorax or abdomen. Regions of interest were placed over composite images of each organ for which activity was visualized to generate time-activity curves. Doses were calculated from residence times using the MIRDOSE3 program. RESULTS: The critical organ for dosimetry is the urinary bladder wall with a dose of 0.0586 +/- 0.0164 mGy/MBq. The dose comes primarily (97.2%) from activity in the urinary bladder contents. The dose is lower than any of the other agents used commonly in PET to assess dopaminergic function. The effective dose equivalent (0.0120 mGy/MBq) is also lower than comparable compounds. CONCLUSION: (18)F-FPCIT has favorable dosimetry when compared with other agents used to study dopaminergic function. Doses as high as 853 MBq (23 mCi) may be given to adult patients and remain within accepted guidelines.     

microPET imaging of glioma integrin {alpha}v{beta}3 expression using (64)Cu-labeled tetrameric RGD peptide.

Integrin alpha(v)beta(3) plays a critical role in tumor-induced angiogenesis and metastasis and has become a promising diagnostic indicator and therapeutic target for various solid tumors. Radiolabeled RGD peptides that are integrin specific can be used for noninvasive imaging of integrin expression level as well as for integrin-targeted radionuclide therapy. METHODS: In this study we developed a tetrameric RGD peptide tracer (64)Cu-DOTA-E{E[c(RGDfK)](2)}(2) (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid) for PET imaging of integrin alpha(v)beta(3) expression in female athymic nude mice bearing the subcutaneous UG87MG glioma xenografts. RESULTS: The RGD tetramer showed significantly higher integrin binding affinity than the corresponding monomeric and dimeric RGD analogs, most likely due to a polyvalency effect. The radiolabeled peptide showed rapid blood clearance (0.61 +/- 0.01 %ID/g at 30 min and 0.21 +/- 0.01 %ID/g at 4 h after injection, respectively [%ID/g is percentage injected dose per gram]) and predominantly renal excretion. Tumor uptake was rapid and high, and the tumor washout was slow (9.93 +/- 1.05 %ID/g at 30 min after injection and 4.56 +/- 0.51 %ID/g at 24 h after injection). The metabolic stability of (64)Cu-DOTA-E{E[c(RGDfK)](2)}(2) was determined in mouse blood, urine, and liver and kidney homogenates at different times after tracer injection. The average fractions of intact tracer in these organs at 1 h were approximately 70%, 58%, 51%, and 26%, respectively. Noninvasive microPET studies showed significant tumor uptake and good contrast in the subcutaneous tumor-bearing mice, which agreed well with the biodistribution results. Integrin alpha(v)beta(3) specificity was demonstrated by successful blocking of tumor uptake of (64)Cu-DOTA-E{E[c(RGDfK)](2)}(2) in the presence of excess c(RGDyK) at 1 h after injection. The highest absorbed radiation doses determined for the human reference adult were received by the urinary bladder wall (0.262 mGy/MBq), kidneys (0.0296 mGy/MBq), and liver (0.0242 mGy/MBq). The average effective dose resulting from a single (64)Cu-DOTA-E{E[c(RGDfK)](2)}(2) injection was estimated to be 0.0164 mSv/MBq. CONCLUSION: The high integrin and avidity and favorable biokinetics make (64)Cu-DOTA-E{E[c(RGDfK)](2)}(2) a promising agent for peptide receptor radionuclide imaging and therapy of integrin-positive tumors.     

Rhenium-188-Labeled DTPA: a new radiopharmaceutical for intravascular radiation therapy

Balloon angioplasty is a standard treatment for artherosclerotic coronary artery disease. However, its clinical value is reduced by a high restenosis rate. A new concept in preventing restenosis is the use of a liquid-filled balloon containing a beta-emitting radioisotope. In this study, we performed biodistribution studies of Re-188 perrhenate and Re-188 diethylenetriaminopentaacetate (DTPA) to assess the resulting organ dose values in the event of balloon rupture if these agents are used for the clinical inhibition of restenosis after percutaneous transluminal coronary angioplasty (PTCA). After injecting Re-188 preparations intravenously, rats were killed at 10 min, 30 min, 60 min, 2 h, and 6 h ( n =5 per group). Tissue concentrations were calculated and expressed as percent injected dose per gram or per milliliter (%ID/g or %ID/mL). In addition, urine excretion and thyroid gland uptake were evaluated in rats ( n=5 per group) with a gamma camera after administration of 37 MBq (1 mCi) of each agent. Our data showed that both agents were excreted primarily via urine. However, the excretion of Re-188 DTPA was much faster than that of Re-188 perrhenate via the urinary system. The biodistribution data revealed that radioactivity levels in the stomach and the thyroid gland were high in the perrhenate group but low in the Re-188 DTPA group. The concentration levels in other tissues including lung, liver, testis, muscle, and blood were low throughout this study for both agents. The thyroid radiation value in the Re-188 perrhenate group was 0.163 mGy/MBq, which was much higher than that of the Re-188 DTPA group (0.0167 mGy/MBq). The stomach radiation value was as high as 0.127 mGy/MBq for Re-188 perrhenate, compared with 0.013 mGy/MBq for Re-188 DTPA. In conclusion, in the event of balloon rupture, the release of Re-188 DTPA results in lower radiation doses than Re-188 perrhenate, especially to the thyroid gland and the stomach. Our data suggest that Re-188 DTPA is a useful radiopharmaceutical for endovascular irradiation.     

Biodistribution and imaging with (123)I-ADAM: a serotonin transporter imaging agent.

2-((2-((Dimethylamino)methyl)phenyl)thio)-5-(123)I-iodophenylamine ((123)I-ADAM) is a new radiopharmaceutical that selectively binds the central nervous system serotonin transporters. The purpose of this study was to measure its whole-body biokinetics and estimate its radiation dosimetry in healthy human volunteers. The study was conducted within a regulatory framework that required its pharmacologic safety to be assessed simultaneously. METHODS: The sample included 7 subjects ranging in age from 22 to 54 y old. An average of 12.7 whole-body scans were acquired sequentially on a dual-head camera for up to 50 h after the intravenous administration of 185 MBq (5 mCi) (123)I-ADAM. The fraction of the administered dose in 13 regions of interest (ROIs) was quantified from the attenuation-corrected geometric mean counts in conjugate views. Multiexponential functions were iteratively fit to each time-activity curve using a nonlinear, least-squares regression algorithm. These curves were numerically integrated to yield source organ residence times. Gender-specific radiation doses were then estimated with the MIRD technique. SPECT brain scans obtained 3 h after injection were evaluated using an ROI analysis to determine the range of values for the region to cerebellum. RESULTS: There were no pharmacologic effects of the radiotracer on any of the subjects, including no change in heart rate, blood pressure, or laboratory results. Early planar images showed differentially increased activity in the lungs. SPECT images demonstrated that the radiopharmaceutical localized in the midbrain in a distribution that is consistent with selective transporter binding. The dose-limiting organ in both men and women was the distal colon, which received an average of 0.12 mGy/MBq (0.43 rad/mCi) (range, 0.098-0.15 mGy/MBq). The effective dose equivalent and effective dose for (123)I-ADAM were 0.037 +/- 0.003 mSv/MBq and 0.036 +/- 0.003 mSv/MBq, respectively. The mean adult male value of effective dose for (123)I-ADAM is similar in magnitude to that of (111)In-diethylenetriaminepentaacetic acid (0.035 mGy/MBq), half that of (111)In-pentetreotide (0.81 mGy/MBq), and approximately twice that of (123)I-inosine 5'-monophosphate (0.018 mGy/MBq). The differences in results between this study and a previous publication are most likely due to several factors, the most prominent being this dataset used attenuation correction of the scintigraphic data. Region-to-cerebellum ratios for the brain SPECT scans were 1.95 +/- 0.13 for the midbrain, 1.27 +/- 0.10 for the medial temporal regions, and 1.11 +/- 0.07 for the striatum. CONCLUSION: (123)I-ADAM may be a safe and effective radiotracer for imaging serotonin transporters in the brain and the body.     

Biodistribution and dosimetry study of 123I-rh-annexin V in mice and humans

This study reports on the optimization of the labelling procedure of clinical grade 123I-rh-annexin V and on the investigation of the biodistribution and dosimetry of 123I-rh-annexin V, a tracer proposed for the study of apoptosis in mice and humans. Research grade 123I-rh-annexin V was prepared as described previously, whereas clinical grade 123I-rh-annexin V was prepared according to a modified IodoGen method. NMRI mice, 3-4 weeks of age, received research grade 123I-rh-annexin V (74.0+/-3.7 kBq/mouse) by intravenous (i.v.) injection and killed at preset time points. Afterwards, the collected organs, blood, urine and faeces were counted for radioactivity and determined as %ID/g tissue or %ID over time. Secondly, six volunteers with normal liver and kidney function underwent whole-body scans up to 21 h after i.v. injection of clinical grade 123I-rh-annexin V (345+/-38 MBq). Time-activity curves were generated for the organs of interest, e.g., thyroid, heart, liver, kidneys and whole body, by fitting the organ specific geometric mean counts, obtained from region of interest analysis of acquired images in humans. The MIRD formulation was applied to calculate the absorbed radiation doses for various organs. Clinical grade 123I-rh-annexin V was obtained in radiochemical yields of 87.0+/-6.5% and radiochemical purities >98%. In mice, research grade 123I-rh-annexin V accumulated primarily in liver, kidney, stomach and lung tissue, limiting its usefulness for imaging of ongoing apoptosis in the abdominal and thoracic region. Clearance was predominantly urinary. In humans, acquired images with the clinical grade radioligand showed low lung uptake, resulting in good imaging conditions for the thoracic region. On the other hand, delayed imaging of the abdominal region was impeded due to extensive bowel activity. The highest absorbed doses were received by the thyroid, the kidneys, the heart wall, the liver and bone surfaces. The average effective dose of 123I-rh-annexin V was estimated to be 0.02 mSv.MBq-1. The amount of 123I-rh-annexin V required for in vivo imaging, results in an acceptable effective dose to the patient.     

Pharmacokinetics and radiation dosimetry estimation of O-(2-[18F]fluoroethyl)-L-tyrosine as oncologic PET tracer.

An easy-to-automate synthetic procedure and the kinetics and radiation dosimetry of O-(2-[18F]fluoroethyl)-L-tyrosine (FET), a recently developed amino acid tracer with potential applications in tumor imaging with PET, are described. FET was prepared in high radiochemical yield, 20-25% with no decay correction, and radiochemical purity of more than 95% in less than 60min synthesis time by a modified two-step procedure and manual operation. The kinetics and radiation dosimetry of FET were evaluated by using mice biodistribution data and the medical internal radiation dosimetry (MIRD) method. The bone (total) was the organ receiving the highest dose, 4.78x10(-3)mGy/MBq, and the brain and the whole body received the lowest dose, 1.6x10(-3)mGy/MBq, respectively. The effective dose was 9.0x10(-3)mSv/MBq. The data show that a 370-MBq (10mCi) injection of FET leads to an estimated effective dose of 3.3mSv and an estimated dose to the whole body of 0.6mGy. The potential radiation risks associated with this study are well within accepted limits.     

Biodistribution and radiation dosimetry of [18F]F-PEB in nonhuman primates

INTRODUCTION: The metabotropic glutamate receptor subtype 5 (mGluR5) is distributed throughout the central nervous system (CNS), and has been suggested to be a potential target for several CNS disorders suchas Parkinson's disease, pain, anxiety, depression, schizophrenia, and addiction. We report here on the rhesus monkey biodistribution and radiation dosimetry of [F]3-fluoro-5-[(pyridine-3-yl)ethynyl]benzonitrile, [F]F-PEB, a mGluR5 positron emission tomography (PET) radiotracer. METHODS: Three male and two female rhesus monkeys were imaged using the Discovery ST PET/computed tomography scanner. A total of 25 whole body PET emissions were acquired over 3 h (23 emissions in one subject). Regions of interest were drawn in the brain, lungs, heart, liver, spleen, bladder, and testes. The absorbed radiation dose was calculated using OLINDA v1. RESULTS: At the end of the imaging session, 45% of the [F]F-PEB activity had been excreted by the liver and into the gastrointestinal tract and 10% had been excreted into the urinary bladder. When extrapolating to the adult human, the largest absorbed radiation doses were located in the upper large intestine (males: 0.18 mGy/MBq, females: 0.20 mGy/MBq) and small intestine (males: 0.16 mGy/MBq, females: 0.19 mGy/MBq). Effective radiation dose was 0.033 mSv/MBq for males and 0.034 mSv/MBq for females, similar to many other [F] ligands. CONCLUSION: The effective radiation dose of [F]F-PEB obtained from rhesus is similar to many other clinically utilized [F] ligands.     

In vitro and in vivo evaluation of direct rhenium-188-labeled anti-CD52 monoclonal antibody alemtuzumab for radioimmunotherapy of B-cell chronic lymphocytic leukemia

Alemtuzumab (Campath, Berlex) is a humanized IgG1 rat monoclonal antibody directed against the cell surface CD52 antigen, found on lymphocytes and monocytes. It is being developed for the treatment of chronic lymphocytic leukemia (CLL), autoimmune disease and for the prevention of transplant rejection. This study focused on synthesis, quality control, in vitro evaluation and biodistribution of (188)Re-labeled alemtuzumab for radioimmunotherapy of B-cell CLL. (188)Re-alemtuzumab was synthesized using a direct radiolabeling method. Reduction of the intramolecular disulfide bonds of the antibody was performed with tris-(carboxyethyl)-phosphine (Pierce), using a 1:60 molar excess. Reaction took place at room temperature for 20 min. A PD-10 desalting column was used to purify the reduced antibody from excess phospine. Complexation and transchelation of (188)ReO(4)(-) was achieved using sodium gluconate as weak chelator and SnCl(2) as reducing agent. Quality control was done using instant thin-layer chromatography. Binding assays were performed on a CD52-positive cell line (HuT-78). Female NMRI mice were injected intravenously with 20 microg radiolabeled alemtuzumab and killed at preset time intervals for biodistribution studies. Tissues were dissected, weighed and counted for determination of radioactivity. Data were expressed as percentage injected activity per gram of tissue (% IA/g tissue) or as percentage injected activity (% IA). (188)Re-alemtuzumab was prepared achieving high radiochemical yields. Labeling efficiency of more than 95% can be obtained using optimal reaction conditions. (188)Re-alemtuzumab showed good in vitro stability, remaining intact at 24 h after radiolabeling. In mice, (188)Re-alemtuzumab showed high uptake in the blood (25.10+/-1.36% IA at 1 h p.i.), followed by a biexponential clearance (t(1/2alpha)=4.790 h and t(1/2beta)=55.45 h). Increased uptake was observed in kidneys and heart (9.29+/-0.46% IA/g in kidneys and 6.10+/-1.82% IA/g in heart at 1 p.i.). The highest absorbed radiation dose was received by the kidneys (0.159-3.26 mGy/MBq) and heart wall (0.0705-0.132 mGy/MBq). The predicted radiation dose for the total body was in the range of 0.0459-0.0529 mGy/MBq. The effective dose for the human reference adult was estimated to be approximately 0.0486-0.195 mSv/MBq. (188)Re-alemtuzumab can be prepared with high radiochemical yield and purity and showed good in vitro behavior and favorable biodistribution. Therefore, (188)Re-alemtuzumab would be an ideal candidate for radioimmunotherapy of chronic lymphocytic leukemia.     

Intraorgan biodistribution and dosimetry of 153Sm-ethylenediaminetetramethylene phosphonate in juvenile rabbit tibia: implications for targeted radiotherapy of osteosarcoma.

Targeted radiotherapy using 153Sm-ethylenediaminetetramethylene phosphonate (153Sm-EDTMP) is currently under investigation for treatment of primary osteosarcoma. Human osteosarcoma most frequently occurs in skeletally immature individuals, and previous studies in a juvenile rabbit model demonstrated that clinically significant damage to developing physeal cartilage might occur as a result of systemic 153Sm-EDTMP therapy. The aim of this study was to determine the distribution of 153Sm-EDTMP within the tibias of juvenile rabbits and estimate the radiation-absorbed doses delivered to the physeal cartilage. METHODS: Eight-week-old New Zealand White rabbits were injected intravenously with 7.57 kBq (280 microCi) of 153Sm-EDTMP. At 21 h after injection, the biodistribution of 153Sm in the epiphysis, metaphysis, diaphysis, and red marrow of the tibia was obtained. Two-dimensional digital autoradiography was performed on 2-mm sections of tibias for qualitative comparison with the biodistribution data. Self-tissue and cross-tissue absorbed doses were calculated using absorbed fractions generated by the Monte Carlo particle transport code MCNP-4C. RESULTS: The highest uptakes (percentage injected dose per gram [%ID/g] of tissue) of 153Sm, 1.99-2.56 %ID/g, were found in the proximal and distal metaphyses, 70%-73% of which localized within 3 mm of the physeal cartilage. The second highest tissues of uptake were the proximal and distal epiphyses, at 0.33-0.62%ID/g. Digital autoradiography imaging confirmed that the majority of 153Sm deposited in the tibia localized to these tissues. Radiation-absorbed doses to the proximal and distal metaphyses were 183 and 130 mGy/MBq, respectively, and those to the proximal and distal epiphyses were 141 and 43.4 mGy/MBq, respectively. These tissues represented the only source compartments contributing to the physeal cartilage doses of 50.0 mGy/MBq for the proximal physis and 39.2 mGy/MBq for the distal physis. CONCLUSION: The 153Sm absorbed doses to the physeal cartilage were consistent with values that can cause dose-limiting damage to rapidly proliferating and differentiating chondrocytes. The pronounced uptake in the juvenile epiphysis indicates that the proliferating zone of the physis can be irradiated from multiple areas, which could increase the expression and degree of radiation damage. Further investigation of the effects of 153Sm-EDTMP on immature physeal cartilage is warranted to develop optimized treatment regimens.     

Safety, biodistribution, and dosimetry of 99mTc-HYNIC-annexin V, a novel human recombinant annexin V for human application.

99mTc-hydrazinonicotinamido (HYNIC)-annexin V is a novel tracer for in vivo imaging of apoptosis. The present study on humans was performed to investigate the safety of (99m)Tc-HYNIC-annexin V and to quantify the biodistribution and radiation dose. METHODS: Six healthy, male volunteers participated in the study. A dual-head gamma camera was used to acquire conjugate anterior and posterior views. Imaging started with a transmission scan using a (57)Co-flood source to obtain a map of the local thickness of the volunteer. Approximately 250 MBq of (99m)Tc-HYNIC-annexin V were injected intravenously, directly followed by a 30-min dynamic study. Whole-body scans were obtained at about 30 min, 3 h, 6 h, and 24 h after injection. Organ uptake was determined after correction for background, scatter, and attenuation. The MIRDOSE3.1 program was used to calculate organ-absorbed doses and effective dose. Signs of adverse effects were investigated by monitoring renal and liver function, hematology, blood coagulation, and vital signs (blood pressure, pulse, respiration rate, temperature, and electrocardiogram). RESULTS: The kidneys accumulated 49.7 +/- 8.1 percentage injected dose (%ID) at 3 h after injection; the liver, 13.1 +/- 1.0 %ID; the red marrow, 9.2 +/- 1.8 %ID; and the spleen, 4.6 +/- 1.6 %ID. More than 90% of the blood activity was cleared with a half-life of 24 +/- 3 min. The biologic half-life of the activity registered over the total body was long (69 +/- 7 h). Excretion of the activity was almost exclusively through the urine (22.5 +/- 3.5 %ID at 24 h), and hardly any activity was seen in the bowel or feces. Absorbed doses were found to be 196 +/- 31 micro Gy/MBq for the kidneys, 41 +/- 12 micro Gy/MBq for the spleen, 16.9 +/- 1.3 micro Gy/MBq for the liver, and 8.4 +/- 0.9 micro Gy/MBq for the red marrow. The effective dose was 11.0 +/- 0.8 micro Sv/MBq, or 2.8 +/- 0.2 mSv for the average injected activity of 250 MBq. No adverse effects were observed. CONCLUSION: (99m)Tc-HYNIC-annexin V is a safe radiopharmaceutical, having a favorable biodistribution for imaging of apoptosis in the abdominal as well as thoracic area with an acceptable radiation dose.