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This paper presents standardized methods for performing dose calculations for radiopharmaceuticals. Various steps in the process are outlined, with some specific examples given. Special models for calculating time-activity integrals (urinary bladder, intestines) are also reviewed. This article can be used as a template for designing and executing kinetic studies for calculating radiation dose estimates from animal or human data., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

This paper presents standardized methods for collecting data to be used in performing dose calculations for radiopharmaceuticals. Various steps in the process are outlined, with some specific examples given. This document can be used as a template for designing and executing kinetic studies for calculating radiation dose estimates, from animal or human data., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

With the recent approval of 177 Lu-DOTATATE for use in gastroenteropancreatic neuroendocrine tumors, access to peptide receptor radionuclide therapy is increasing. Representatives from the North American Neuroendocrine Tumor Society and the Society of Nuclear Medicine and Molecular Imaging collaborated to develop a practical consensus guideline for the administration of 177 Lu-DOTATATE. In this paper, we discuss patient screening, maintenance somatostatin analog therapy requirements, treatment location and room preparation, drug administration, and patient release as well as strategies for radiation safety, toxicity monitoring, management of potential complications, and follow-up. Controversies regarding the role of radiation dosimetry are discussed as well. This document is designed to provide practical guidance on how to safely treat patients with this therapy., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

A compendium of about 100 radiopharmaceuticals, based on the OLINDA/EXM version 2.0 software, is presented. A new generation of voxel-based, realistic human computational phantoms developed by the RADAR committee of the Society of Nuclear Medicine and Molecular Imaging, based on 2007 recommendations of the International Commission on Radiological Protection, was used to develop the dose estimates, and the most recent biokinetic models were used as well. These estimates will be made available in electronic form and can be modified and updated as models are changed and as new radiopharmaceuticals are added., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Current standard values of fetal dosimetry deriving from 18 F-FDG injection in pregnant women are estimated from animal data. The present communication offers a revision of fetal dosimetry values calculated from recently published human data, in which fetal 18 F-FDG uptake was directly observed in vivo. The final doses were obtained from the observed time-integrated activity coefficients and a new generation of anthropomorphic voxel-based pregnancy phantoms., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Data from the literature show that the fetal absorbed dose from 18 F-FDG administration to the pregnant mother ranges from 0.5E-2 to 4E-2 mGy/MBq. These figures were, however, obtained using different quantification techniques and with basic geometric anthropomorphic phantoms. The aim of this study was to refine the fetal dose estimates of published as well as new cases using realistic voxel-based phantoms., Methods: The 18 F-FDG doses to the fetus (n = 19; 5-34 wk of pregnancy) were calculated with new voxel-based anthropomorphic phantoms of the pregnant woman. The image-derived fetal time-integrated activity values were combined with those of the mothers' organs from the International Commission on Radiological Protection publication 106 and the dynamic bladder model with a 1-h bladder-voiding interval. The dose to the uterus was used as a proxy for early pregnancy (up to 10 wk). The time-integrated activities were entered into OLINDA/EXM 1.1 to derive the dose with the classic anthropomorphic phantoms of pregnant women, then into OLINDA/EXM 2.0 to assess the dose using new voxel-based phantoms., Results: The average fetal doses (mGy/MBq) with OLINDA/EXM 2.0 were 2.5E-02 in early pregnancy, 1.3E-02 in the late part of the first trimester, 8.5E-03 in the second trimester, and 5.1E-03 in the third trimester. The differences compared with the doses calculated with OLINDA/EXM 1.1 were +7%, +70%, +35%, and -8%, respectively., Conclusion: Except in late pregnancy, the doses estimated with realistic voxelwise anthropomorphic phantoms are higher than the doses derived from old geometric phantoms. The doses remain, however, well below the threshold for any deterministic effects. Thus, pregnancy is not an absolute contraindication of a clinically justified 18 F-FDG PET scan., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: PET has been used to examine changes in neurotransmitter concentrations in the living brain. Pioneering PET studies on the dopamine system have used D2 and D3 receptor (D2/D3) antagonists such as (11)C-raclopride. However, more recently developed agonist radioligands have shown enhanced sensitivity to endogenous dopamine. A limitation of available agonist radioligands is that they incorporate the short-lived radioisotope (11)C. In the current study, we developed the (18)F-labeled D2/D3 receptor agonist (R)-(-)-2-(18)F-fluoroethoxy-N-n-propylnorapomorphine ((18)F-MCL-524)., Methods: In total, 10 PET measurements were conducted on 5 cynomolgus monkeys. Initially, the binding of (18)F-MCL-524 was compared with that of (11)C-MNPA in 3 monkeys. Second, the specificity of (18)F-MCL-524 binding was examined in pretreatment studies using raclopride (1.0 mg/kg) and d-amphetamine (1.0 mg/kg). Third, a preliminary kinetic analysis was performed using the radiometabolite-corrected arterial input function of the baseline studies. Finally, 2 whole-body PET measurements were conducted to evaluate biodistribution and radiation dosimetry after intravenous injection of (18)F-MCL-524., Results: (18)F-MCL-524 entered the brain and provided striatum-to-cerebellum ratios suitable for reliable quantification of receptor binding using the multilinear reference tissue model. Mean striatal nondisplaceable binding potential (BPND) values were 2.0 after injection of (18)F-MCL-524 and 1.4 after (11)C-MNPA. The ratio of the BPND values of (18)F-MCL-524 and (11)C-MNPA was 1.5 across striatal subregions. After administration of raclopride and d-amphetamine, the (18)F-MCL-524 BPND values were reduced by 89% and 56%, respectively. Preliminary kinetic analysis demonstrated that BPND values obtained with the 1-tissue- and 2-tissue-compartment models were similar to values obtained with the multilinear reference tissue model. Estimated radiation doses were highest for gallbladder (0.27 mSv/MBq), upper large intestine (0.19 mSv/MBq), and small intestine (0.17 mSv/MBq). The estimated effective dose was 0.035 mSv/MBq., Conclusion: The (18)F-labeled agonist (18)F-MCL-524 appears suitable for quantification of D2/D3 receptor binding in vivo, and the results encourage extension to human studies. The longer half-life of (18)F makes (18)F-MCL-524 attractive for studies on modulation of the dopamine concentration-for example, in combination with simultaneous measurement of changes in blood-oxygen-level-dependent signal using bimodal PET/functional MRI., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: (18)F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ((18)F-FPEB) is a potent and specific radioligand for the metabotropic glutamate receptor subtype 5 (mGluR5). Before undertaking clinical research studies with (18)F-FPEB, we performed studies of human radiation dosimetry., Methods: Serial whole-body scans were obtained in 9 healthy human subjects (5 men, 4 women) for 190-440 min after the intravenous administration of (18)F-FPEB. Radiation doses were estimated using the OLINDA/EXM software., Results: Peak organ doses were to the urinary bladder wall, 0.258 mGy/MBq (0.955 rad/mCi), and gallbladder wall, 0.193 mGy/MBq (0.716 rad/mCi). The effective dose was 0.025 mSv/MBq (0.0922 rem/mCi). The doses to the red marrow and spleen were 0.00797 mGy/MBq (0.0295 rad/mCi) and 0.00709 mGy/MBq (0.0262 rad/mCi), respectively. Reducing the urinary voiding interval to 60 or 90 min lowered the urinary bladder wall dose to 0.0885 mGy/MBq (0.327 rad/mCi) or 0.128 mGy/MBq (0.473 rad/mCi), respectively, and the effective dose to 0.0149 mSv/MBq (0.0551 rem/mCi) or 0.0171 mSv/MBq (0.0634 rem/mCi), respectively., Conclusion: Urinary voiding should be performed during (18)F-FPEB studies to minimize radiation exposure to research subjects., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: A first-in-human phase 1 clinical study was performed on 12 healthy adults with a high-specific-activity carrier-free formulation of (123)I-iobenguane. Clinical data are presented on the behavior of this receptor-targeting imaging agent., Methods: Whole-body and thoracic planar and SPECT imaging were performed over 48 h for calculation of tissue radiation dosimetry and for evaluation of clinical safety and efficacy., Results: A reference clinical imaging database acquired over time for healthy men and women injected with high-specific-activity (123)I-iobenguane showed organ distribution and whole-body retention similar to those of conventional (123)I-iobenguane. The heart-to-mediastinum ratios for the high-specific-activity formulation were statistically higher than for conventional formulations, and the predicted radiation dosimetry estimations for some organs varied significantly from those based on animal distributions., Conclusion: Human normal-organ kinetics, radiation dosimetry, clinical safety, and imaging efficacy provide compelling evidence for the use of high-specific-activity (123)I-iobenguane.

Unlabelled: This phase 1 study was performed to determine the pharmacokinetics and ability to visualize prostate cancer in bone, soft-tissue, and the prostate gland using (123)I-MIP-1072 and (123)I-MIP-1095, novel radiolabeled small molecules targeting prostate-specific membrane antigen., Methods: Seven patients with a documented history of prostate cancer by histopathology or radiologic evidence of metastatic disease were intravenously administered 370 MBq (10 mCi) of (123)I-MIP-1072 and (123)I-MIP-1095 2 wk apart in a crossover trial design. (123)I-MIP-1072 was also studied in 6 healthy volunteers. Whole-body planar and SPECT/CT imaging was performed and pharmacokinetics studied over 2-3 d. Target-to-background ratios were calculated. Absorbed radiation doses were estimated using OLINDA/EXM., Results: (123)I-MIP-1072 and (123)I-MIP-1095 visualized lesions in soft tissue, bone, and the prostate gland within 0.5-1 h after injection, with retention beyond 48 h. Target-to-background ratios from planar images averaged 2:1 at 1 h, 3:1 at 4-24 h, and greater than 10:1 at 4 and 24 h for SPECT/CT. Both agents cleared the blood in a biphasic manner; clearance of (123)I-MIP-1072 was approximately 5 times faster. (123)I-MIP-1072 was excreted in the urine, with 54% and 74% present by 24 and 72 h, respectively. In contrast, only 7% and 20% of (123)I-MIP-1095 had been renally excreted by 24 and 72 h, respectively. Estimated absorbed radiation doses were 0.054 versus 0.110 mGy/MBq for the kidneys and 0.024 versus 0.058 mGy/MBq for the liver, for (123)I-MIP-1072 and (123)I-MIP-1095, respectively., Conclusion: (123)I-MIP-1072 and (123)I-MIP-1095 detect lesions in soft tissue, bone, and the prostate gland at as early as 1-4 h. These novel radiolabeled small molecules have excellent pharmacokinetic and pharmacodynamic profiles and warrant further development as diagnostic and potentially when labeled with (131)I therapeutic radiopharmaceuticals.

Unlabelled: A new generation of reference computational phantoms, based on image-based models tied to the reference masses defined by the International Commission on Radiological Protection (ICRP) for dose calculations, is presented., Methods: Anatomic models based on nonuniform rational b-spline modeling techniques were used to define reference male and female adults, 15-y-olds, 10-y-olds, 5-y-olds, 1-y-olds, newborns, and pregnant women at 3 stages of gestation, using the defined reference organ masses in ICRP publication 89. Absorbed fractions and specific absorbed fractions for internal emitters were derived using standard Monte Carlo radiation transport simulation codes., Results: Differences were notable between many pairs of organs in specific absorbed fractions because of the improved realism of the models, with adjacent organs usually closer and sometimes touching. Final estimates of absorbed dose for radiopharmaceuticals, for example, were only slightly different overall, as many of the differences were small and most pronounced at low radiation energies. Some new important organs were defined (salivary glands, prostate, eyes, and esophagus), and the identity of a few gastrointestinal tract organs changed., Conclusion: A new generation of reference models for standardized internal and external dose calculations has been defined. The models will be implemented in standardized software for internal dose calculations and be used to produce new standardized dose estimates for radiopharmaceuticals and other applications.

Unlabelled: 2-((2S,5R,8S,11S)-5-benzyl-8-(4-((2S,3R,4R,5R,6S)-6-((2-(4-(3-(18)F-fluoropropyl)-1H-1,2,3-triazol-1-yl)acetamido)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamido)butyl)-11-(3-guanidinopropyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan-2-yl)acetic acid ((18)F-RGD-K5) has been developed as an α(v)β(3) integrin marker for PET. The purpose of this study was to determine the biodistribution and estimate the radiation dose from (18)F-RGD-K5 using whole-body PET/CT scans in monkeys and humans., Methods: Successive whole-body PET/CT scans were obtained after intravenous injection of (18)F-RGD-K5 in 3 rhesus monkeys (167 ± 19 MBq) and 4 healthy humans (583 ± 78 MBq). In humans, blood samples were collected between the PET/CT scans, and stability of (18)F-RGD-K5 was assessed. Urine was also collected between the scans, to determine the total activity excreted in urine. The PET scans were analyzed to determine the radiotracer uptake in different organs. OLINDA/EXM software was used to calculate human radiation doses based on human and monkey biodistributions., Results: (18)F-RGD-K5 was metabolically stable in human blood up to 90 min after injection, and it cleared rapidly from the blood pool, with a 12-min half-time. For both monkeys and humans, increased (18)F-RGD-K5 uptake was observed in the kidneys, bladder, liver, and gallbladder, with mean standardized uptake values at 1 h after injection for humans being approximately 20, 50, 4, and 10, respectively. For human biodistribution data, the calculated effective dose was 31 ± 1 μSv/MBq, and the urinary bladder wall had the highest absorbed dose at 376 ± 19 μGy/MBq using the 4.8-h bladder-voiding model. With the 1-h voiding model, these doses reduced to 15 ± 1 μSv/MBq for the effective dose and 103 ± 4 μGy/MBq for the absorbed dose in the urinary bladder wall. For a typical injected activity of 555 MBq, the effective dose would be 17.2 ± 0.6 mSv for the 4.8-h model, reducing to 8.3 ± 0.4 mSv for the 1-h model. For monkey biodistribution data, the effective dose to humans would be 22.2 ± 2.4 mSv for the 4.8-h model and 12.8 ± 0.2 mSv for the 1-h model., Conclusion: The biodistribution profile of (18)F-RGD-K5 in monkeys and humans was similar, with increased uptake in the bladder, liver, and kidneys. There was rapid clearance of (18)F-RGD-K5 through the renal system. The urinary bladder wall received the highest radiation dose and was deemed the critical organ. Both whole-body effective dose and bladder dose can be reduced by more frequent voiding. (18)F-RGD-K5 can be used safely for imaging α(v)β(3) integrin expression in humans.

Unlabelled: The aim of this study was to evaluate the quantification, biodistribution, and radiation dosimetry of the novel dopamine transporter (DAT) radioligand (18)F-(2S,3S)-methyl 8-((E)-4-fluorobut-2-en-1-yl)-3-(p-tolyl)-8-azabicyclo[3.2.1]octane-2-carboxylate ((18)F-LBT-999) in nonhuman primates., Methods: The brain study was conducted in 4 female rhesus monkeys. PET measurements were conducted for 243 min using the high-resolution research tomograph (HRRT) with the measurement of the metabolite-corrected arterial input function and protein binding. Quantification was performed with kinetic analysis using 2-tissue- and 1-tissue-compartment models, with Logan graphical analysis and with different reference tissue models. The outcome measures were total distribution volume (V(T)), nondisplaceable distribution volume (V(ND)), binding potential relative to the free concentration of radioligand in plasma (BP(F)), and binding potential relative to the concentration of nondisplaceable radioligand in tissue (BP(ND)) = V(T) - V(ND)/V(ND) using the cerebellum as a reference region. For the biodistribution and radiation dosimetry, 2 female cynomolgus monkeys were studied. Whole-body PET scans were obtained using a PET/CT system for approximately 250 min. Estimates of the absorbed radiation dose in humans were calculated using OLINDA/EXM software., Results: (18)F-LBT-999 showed good brain uptake (300% standardized uptake value) and regional distribution according to known DAT density. The 2-tissue-compartment model was the preferred model for the quantification. Late peak equilibrium (120-140 min) and slow washout were observed in the striatum, with high variability of V(T), BP(F), and BP(ND). When the different models were compared with the 2-tissue-compartment model, the underestimation of V(T) or BP(ND) was larger in the caudate and putamen than in the midbrain and thalamus. The reference tissue models were suitable for the quantification. The whole-body distribution study showed that the main routes of excretion of (18)F-LBT-999 were the urinary and gastrointestinal systems, with the bladder being the critical organ. Accumulation of (18)F-LBT-999 was found in the bone and skull, with a relatively high dose estimated for the osteogenic cells. The range of calculated effective dose was 0.021-0.022 mSv/MBq., Conclusion: (18)F-LBT-999 seemed to be a suitable PET radioligand for the DAT quantification, particularly for extrastriatal regions. The skull uptake did not seem to be a limitation for brain imaging. The calculated dosimetry estimates based on data in nonhuman primates seemed comparable with those of other clinically used (18)F-labeled radioligands, for example, (18)F-FDG (0.024-0.027 mSv/MBq).

Unlabelled: The purpose of this study was to estimate the fetal radiation exposure resulting from (18)F-FDG PET procedures performed in pregnant patients with malignancies., Methods: Five pregnant patients with a biopsy-proven diagnosis of malignancy who underwent (18)F-FDG PET studies were retrospectively reviewed. All patients underwent PET-only studies (and not PET/CT studies) with a reduced (18)F-FDG dose (except for 1 patient who had a negative pregnancy test immediately before the (18)F-FDG PET procedure but was confirmed to be pregnant a few weeks later), including vigorous hydration and diuresis to minimize radiation exposure to the fetus. One patient underwent (18)F-FDG PET twice during her pregnancy (in the second and third trimesters). Fetal radiation dose was independently assessed for each patient, and an analysis was made of fetal radiation doses using the measurements of activity in the fetuses at various stages of pregnancy., Results: Six (18)F-FDG PET studies in 5 pregnant patients were analyzed. The (18)F-FDG PET scans were obtained in early pregnancy (n = 1), the second trimester (n = 2), and the third trimester (n = 3). The fetal dose exposure from (18)F-FDG PET studies was estimated to range from 1.1 to 2.43 mGy for various trimesters in pregnancy (except for the patient in the early stage of pregnancy, in whom activity in the whole uterus was considered, and the fetal dose was estimated to be 9.04 mGy). All patients delivered healthy infants with no visible abnormalities at term., Conclusion: The fetal radiation dose from (18)F-FDG PET studies is quite low and significantly below the threshold dose for deterministic effects due to radiation exposure to the fetus. The estimated fetal radiation exposure in our cases was slightly lower than existing estimates on fetal dose exposure, and as more data become available, the current fetal dose estimates may have to be modified accordingly. By addressing an important safety issue dealing with performing medically necessary (18)F-FDG PET in pregnant patients, these data are expected to help in the imaging workup of cancer patients during pregnancy.

Unlabelled: The phantoms used in standardized dose assessment are based on a median (i.e., 50th percentile) individual of a large population, for example, adult males or females or children of a particular age. Here we describe phantoms that model instead the influence of obesity on specific absorbed fractions (SAFs) and dose factors in adults., Methods: The literature was reviewed to evaluate how individual organ sizes change with variations in body weight in mildly and severely obese adult men and women. On the basis of the literature evaluation, changes were made to our deformable reference adult male and female total-body models. Monte Carlo simulations of radiation transport were performed. SAFs for photons were generated for mildly and severely obese adults, and comparisons were made to the reference (50th) percentile SAF values., Results: SAFs studied between the obese phantoms and the 50th percentile reference phantoms were not significantly different from the reference 50th percentile individual, with the exception of intestines irradiating some abdominal organs, because of an increase in separation between folds caused by an increase in mesenteric adipose deposits. Some low-energy values for certain organ pairs were different, possibly due only to the statistical variability of the data at these low energies., Conclusion: The effect of obesity on dose calculations for internal emitters is minor and may be neglected in the routine use of standardized dose estimates.

Unlabelled: A systematic evaluation has been performed to study how specific absorbed fractions (SAFs) vary with changes in adult body size, for persons of different size but normal body stature., Methods: A review of the literature was performed to evaluate how individual organ sizes vary with changes in total body weight of normal-stature individuals. On the basis of this literature review, changes were made to our easily deformable reference adult male and female total-body models. Monte Carlo simulations of radiation transport were performed; SAFs for photons were generated for 10th, 25th, 75th, and 90th percentile adults; and comparisons were made to the reference (50th) percentile SAF values., Results: Differences in SAFs for organs irradiating themselves were between 0.5% and 1.0%/kg difference in body weight, from 15% to 30% overall, for organs within the trunk. Differences in SAFs for organs outside the trunk were not greater than the uncertainties in the data and will not be important enough to change calculated doses. For organs irradiating other organs within the trunk, differences were significant, between 0.3% and 1.1%/kg, or about 8%-33% overall., Conclusion: The differences are interesting and can be used to estimate how different patients' dosimetry might vary from values reported in standard dose tables.

Unlabelled: Rodent species are widely used in the testing and approval of new radiopharmaceuticals, necessitating murine phantom models. As more therapy applications are being tested in animal models, calculating accurate dose estimates for the animals themselves becomes important to explain and control potential radiation toxicity or treatment efficacy. Historically, stylized and mathematically based models have been used for establishing doses to small animals. Recently, a series of anatomically realistic human phantoms was developed using body models based on nonuniform rational B-spline. Realistic digital mouse whole-body (MOBY) and rat whole-body (ROBY) phantoms were developed on the basis of the same NURBS technology and were used in this study to facilitate dose calculations in various species of rodents., Methods: Voxel-based versions of scaled MOBY and ROBY models were used with the Vanderbilt multinode computing network (Advanced Computing Center for Research and Education), using geometry and tracking radiation transport codes to calculate specific absorbed fractions (SAFs) with internal photon and electron sources. Photon and electron SAFs were then calculated for relevant organs in all models., Results: The SAF results were compared with values from similar studies found in reference literature. Also, the SAFs were used with standardized decay data to develop dose factors to be used in radiation dose calculations. Representative plots were made of photon electron SAFs, evaluating the traditional assumption that all electron energy is absorbed in the source organs., Conclusion: The organ masses in the MOBY and ROBY models are in reasonable agreement with models presented by other investigators noting that considerable variation can occur between reported masses. Results consistent with those found by other investigators show that absorbed fractions for electrons for organ self-irradiation were significantly less than 1.0 at energies above 0.5 MeV, as expected for many of these small-sized organs, and measurable cross-irradiation was observed for many organ pairs for high-energy electrons (as would be emitted by nuclides such as (32)P, (90)Y, or (188)Re).

Unlabelled: The technical basis for the dose estimates for several radiopharmaceuticals used in nuclear cardiology is reviewed, and cases in which uncertainty has been encountered in the dosimetry of an agent are discussed. Also discussed is the issue of uncertainties in radiation dose estimates and how to compare the relative risks of studies., Methods: Radiation dose estimates (organ absorbed doses and effective doses) from different literature sources were directly compared. Typical values for administered activity per study were used to compare doses that are to be expected in clinical applications., Results: The effective doses for all agents varied from 2 to 15 mSv per study, with the lowest values being seen for (13)N-NH(3) and (15)O-H(2)O studies and the highest values being seen for (201)Tl-chloride studies. The effective doses for (99m)Tc- and (201)Tl-labeled agents differed by about a factor of 2, a factor that is comparable to the uncertainty in individual values. This uncertainty results from the application of standard anthropomorphic and biokinetic models, presumably representative of the exposed population, to individual patients., Conclusion: Considerations such as diagnostic accuracy, ease of use, image quality, and patient comfort and convenience should generally dictate the choice of a radiopharmaceutical, with radiation dose being only a secondary or even tertiary consideration. Counseling of nuclear medicine patients who may be concerned about exposure should include a reasonable estimate of the median dose for the type of examination and administered activity of the radiopharmaceutical; in addition, it should be explained that the theoretic risks of the procedure are orders of magnitude lower than the actual benefits of the examination. Providing numeric estimates of risks from studies to individual patients is inappropriate, given the uncertainties in the dose estimates and the limited predictive power of current dose-risk models in the low-dose (i.e., diagnostic) range.

Unlabelled: Our purpose was to evaluate the safety profile and biodistribution behavior in healthy human volunteers of the new myocardial perfusion tracer bis[(dimethoxypropylphosphanyl)ethyl]ethoxyethylamine N,N'-bis(ethoxyethyl)dithiocarbamato nitrido technetium(V) (99mTc-N-DBODC)., Methods: Ten healthy male volunteers were injected with 99mTc-N-DBODC under both stress and rest conditions. Anterior and posterior planar gamma-camera images were collected at 5, 30, 60, 240, and 1,440 min after injection, with organ uptake quantified by region-of-interest analysis. Tracer kinetics in body fluids were determined by collecting blood and urine samples at different time points., Results: After injection, 99mTc-N-DBODC showed significant accumulation in the myocardium and prolonged retention. Under rest conditions, uptake in the heart, lungs, and liver at 5 min after injection was 1.67% +/- 0.13%, 1.16% +/- 0.07%, and 10.85% +/- 1.72%, respectively, of administered activity. Under stress conditions, heart uptake was significantly higher (2.07% +/- 0.22%). Radioactivity in the liver decreased to 3.64% +/- 0.98% and 2.37% +/- 0.48% at 60 and 240 min, respectively, after injection. This rapid liver clearance led to favorable heart-to-liver ratios, reaching values of 0.74 +/- 0.13 at rest and 1.26 +/- 0.28 during exercise 60 min after tracer administration. Radiation dose estimates were comparable to those obtained with other myocardial perfusion cationic compounds., Conclusion: The high uptake in the myocardium and the fast liver washout of 99mTc-N-DBODC will allow SPECT images of the left ventricle to be acquired early and with excellent quality.

This paper presents a systematic analysis of the inherent uncertainty in internal dose calculations for radiopharmaceuticals. A generic equation for internal dose is presented, and the uncertainty in each of the individual terms is analyzed, with the relative uncertainty of all terms compared. The combined uncertainties in most radiopharmaceutical dose estimates will be typically at least a factor of 2 and may be considerably greater. In therapy applications, if patient-individualized absorbed doses are calculated, with attention being paid to accurate data gathering and analysis and measurement of individual organ volumes, many of the model-based uncertainties can be removed, and the total uncertainty in an individual dose estimate can be reduced to a value of perhaps +/-10%-20%. Radiation dose estimates for different diagnostic radiopharmaceuticals should be appreciated and considered, but small differences in dose estimates between radiopharmaceuticals should not be given too much importance when one is choosing radiopharmaceuticals for general clinical use. Diagnostic accuracy, ease of use, image quality, patient comfort, and other similar factors should predominate in the evaluation, with radiation dose being another issue considered while balancing risks and benefits appropriately.

As a first step in performing patient-specific absorbed dose calculations, it may be necessary to scale dose conversion factors (e.g., S values in the MIRD system or dose factors in the RADAR system) by patient organ mass. The absorbed dose to active marrow is of particular interest for radionuclide therapy. When using the blood-based model of red marrow (RM) absorbed dose estimation, there are only 2 S values of concern, representing RM self-dose and cross-dose terms. Linear mass scaling has generally been performed for the self-dose term, whereas the cross-dose term is considered to be mass independent. We will illustrate that each radionuclide may need to have its mass-based correction determined to assess whether the conventionally used linear mass scaling is appropriate and should be applied not only to the self-dose S value but also to the cross-dose term.

Unlabelled: The Chernobyl accident resulted in a number of cases of thyroid cancer in females under the age of 20 y. Many of these individuals were treated with surgical removal of the thyroid gland followed by 131I ablation of residual thyroid tissue. Epidemiologic evidence demonstrates that 131I treatment for thyroid cancer or hyperthyroidism in adult women confers negligible risk of breast cancer. However, comparable data for younger women do not exist. Studies of external radiation exposure indicate that, for radiation exposures of as low as 0.2-0.7 Gy, the risk of breast cancer is greater for infant and adolescent female breast tissues than for adult female breast tissues., Methods: The effective half-time of 131I measured in athyrotic patients was used together with the OLINDA/EXM computer code to estimate doses to breast tissue in 10-y-old, 15-y-old, and young adult females from ablation treatment., Results: The dose to pediatric and young adult female breast tissue associated with a 5.6-GBq (150 mCi) ablation treatment may range from 0.35 to 0.55 Gy, resulting in a lifetime risk of breast cancer ranging from 2-4 cases per 100 such individuals exposed and a lifetime risk of solid tumors ranging from 8 to 17 solid tumors per 100 such individuals exposed. Administration of multiple ablation treatments, as often occurs with metastases, could result in doses ranging from 0.7 to 1 Gy, with corresponding increases in the lifetime cancer risk., Conclusion: These estimates suggest the need for additional research and a possible need for surveillance of young Chernobyl thyroid cancer patients who received 131I ablation treatment.

Unlabelled: (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.

Unlabelled: The ability to estimate absorbed doses in experimental animals to which radiolabeled material has been administered may be important in explaining and controlling potential radiation toxicity observed during preclinical trials. Most previously reported models for establishing doses to small animals have been stylized and mathematically based. This study establishes dose factors for internal sources in realistic models of a typical mouse and a typical rat, based on image data obtained using a dedicated small-animal CT scanner., Methods: A transgenic mouse (body mass, 27 g) and a Sprague-Dawley rat (body mass, 248 g) were imaged using the dedicated small-animal CT scanner. Identified organs were segmented using computer tools that Vanderbilt University applies to process human images for 3-dimensional dosimetry. Monte Carlo N-particle transport code (MCNP) input files were prepared from the 3-dimensional, voxel-based image data. Using methods established for human studies, radiation transport calculations of absorbed fractions (AFs) were performed using MCNP, version 4C, on the segmented images, and dose conversion factors for several radionuclides were developed., Results: AFs were established at discrete energies for electron and photon sources assumed to be uniformly distributed throughout approximately 10 source and target regions in both models. Electron self-irradiation AFs were significantly less than 1.0 for many organs, at energies above 0.5 MeV, and significant cross irradiation was observed for high-energy electrons, such as those from (90)Y or (188)Re, in many organs. Calculated dose conversion factors reflected these trends and agreed well with the results of other authors who have undertaken similar investigations., Conclusion: The AFs calculated in this study will be useful in determining the dose to organs for mice and rats similar in size to those studied here. The segmented, voxel-based models developed here can be used for external dose calculations as well.

Unlabelled: The OLINDA/EXM version 1.0 personal computer code was created as a replacement for the widely used MIRDOSE3.1 code. This paper documents the basic function of the code and how it is similar to and different from the MIRDOSE software., Methods: After creation of the code and alpha- and beta-testing phases, a premarket notification submission (510(k)) was filed with the Food and Drug Administration to permit marketing of the code. Permission was granted in June 2004, and the code is currently being distributed through Vanderbilt University. Not all of the technical details of the dosimetry methods have been shown here, as they have been previously documented., Results: Agreement of doses between the MIRDOSE3.1 and OLINDA/EXM codes was good, within 1%-2% in most cases., Conclusion: The extensive testing of the OLINDA/EXM code, based on comparison with literature-established dose calculations and with the widely tested and accepted MIRDOSE3.1 code, should give users confidence in its output. The OLINDA/EXM code should be easy for MIRDOSE users to adopt and for new users to understand. It will be useful in standardizing and automating internal dose calculations, assessing doses in clinical trials with radiopharmaceuticals, making theoretic calculations for existing pharmaceuticals, teaching, and other purposes.

Unlabelled: Serotonin 1A receptors have been implicated in a variety of conditions including depression, suicidal behavior, and aggression. Dose estimates for current human studies are based on data from rat dosimetry studies. We report the biodistribution and dosimetry of the PET serotonin 1A antagonist 11C-WAY100,635 in humans., Methods: PET studies of 6 healthy human volunteers (3 male, 3 female) were acquired after a bolus injection of 11C-WAY100,635. Transmission scans of 3.5 min were obtained at each bed position before injection, and emission scans then were collected in 2-dimensional mode over 8 bed positions. Regions of interest were drawn around the brain, left and right lungs, heart, liver, stomach wall, gallbladder, left and right kidneys, spleen, and urinary bladder. Because no fluid was removed from the subjects, whole-body radioactivity was calculated using the injected dose and a calibration factor determined from a cylinder phantom. The area under the curve for each region of interest was determined by trapezoidal integration of the first 3 points, with subsequent points fit by a decreasing monoexponential. The area under the curve was then divided by counts in the whole body, and the resulting residence times were entered into the MIRDOSE3 program., Results: Primary elimination was via kidneys to the urinary bladder. There were no sex differences in organ residence times. The urinary bladder wall was the organ with the highest estimated radiation dose (1.94 x 10(-1) +/- 3.57 x 10(-2) mGy/MBq). Except for the kidney and bladder wall, correlation was good between human dosimetry estimates and estimates reported previously from rats. The human dosimetry was 6.6 and 60.6 times higher in the kidneys and urinary bladder wall, respectively, than estimates from rats., Conclusion: The urinary bladder wall is the critical organ for 11C-WAY100,635 in humans. In the United States, according to Radioactive Drug Research Committee guidelines a single dose cannot exceed 300 MBq in a man and 227 MBq in a woman, with up to 3 such injections permitted per annum.

Unlabelled: Revised radiation dosimetry estimates for 201Tl-thallous chloride have been developed using new data specifically acquired to address the issue of testicular uptake of this agent and through reevaluation of extant data for biodistribution in other organs., Methods: Quantitative testicular scintigraphy data of sequestered testes (body-background shielded) were obtained from 28 patients (56 studies) injected with 201Tl-thallous chloride at peak exercise. Previously published data for 15 patients injected at maximal exercise were reanalyzed to obtain updated biodistribution parameters for designated organs. Radiation dose was calculated according to the MIRD schema. Radiation dose to testes as a function of age was determined. Comparisons are made between organ dose estimates derived in this study and those previously published. The dose contributions of possible contaminants (200Tl, 202Tl, 203Pb) have been included. Estimates are provided of the dose component from these contaminants if injected at the time of the maximum recommended 5-d shelf life (as opposed to at the designated calibration time)., Results: The radiation dose per unit administered activity to adult testes calculated in this study of 0.21 mGy/MBq (0.77 rad/mCi) is approximately a factor of 2 less than the value of 0.45 mGy/MBq (1.7 rad/mCi) previously accepted. The revised dose estimates for other organs show less variation from published values. The effective dose determined in this work is approximately 0.16 mSv/MBq (0.60 rem/mCi). Under the assumption of similar biokinetics as for the adult, the testes dose for children increases significantly as age decreases with a value of 7.5 mGy/MBq (28 rad/mCi) for a newborn. Contributions from radiocontaminants that may be encountered in the preparation of 201Tl-thallous chloride are shown to range from a fraction of a percent up to approximately 20% of the total dose for some organs, with the higher values arising from the long half-life contaminant 202Tl after a 5-d shelf life., Conclusion: It is recommended that the dose values determined in this study be used when estimating the radiation dose to the adult testes from intravenous administration of 201Tl-thallous chloride. The potential for increased radiation dose per administered activity to the testes at younger ages should be evaluated before performing procedures on children. The presence of radiocontaminants in the product should be considered when estimating radiation dose and may add a significant contribution to dose dependent on the specific radionuclide and concentration at the time of administration.

Unlabelled: Standardization of marrow dosimetry is of considerable importance when estimating dose-response for a multicentered clinical trial involving radionuclide therapy. However, it is only within the past five years that the intercomparison of marrow dosimetry results among separate clinical trials that use the same agent has become scientifically feasible. In this work, we have analyzed reported marrow dosimetry results from radioimmunotherapy trials and recalculated marrow absorbed doses at a central facility using a standard blood model with patient-specific source data. The basic approach used in the American Association of Physicists in Medicine (AAPM)/Sgouros marrow dosimetry methodology was common to calculation performed at all participating institutions, including the central facility. Differences in dose estimates associated with starting assumptions and the exact implementation of the AAPM/Sgouros calculation methodology used by the source institutions and the central facility were quantified and compared., Methods: Data from 22 patients enrolled in radiolabeled antibody clinical trials were randomly selected from 7 participating institutions for the assessment of marrow dose. The analysis was restricted to those patients who were treated with 131I- or 186Re-labeled antibody and had no marrow involvement. Calculation of bone marrow dose at each participating institution was unique to the trial or institution, but all used some form of the AAPM/Sgouros blood model approach. The central facility adopted a marrow dosimetry model based on the AAPM/Sgouros model for radiolabeled antibodies using the standard MIRD approach to the remainder-of-body contribution. A standardized approach to account for variations in patient mass was used for the remainder-of-body component. To simplify clinical implementation, regional marrow uptake and time-dependent changes in the marrow-to-blood concentration ratio were not included. Methods of formatting the collection of standard datasets useful in defining dose-response parameters are also presented., Results: Bone marrow doses were calculated according to the method described for each of the 22 patients based on the patient-specific data supplied by the participating institutions. These values were then individually compared with the marrow doses originally reported by each institution. Comparison of the two calculation methods was expressed as a ratio of the marrow doses for each patient. The mean ratio for the dose estimates at the participating institution calculation compared with the central laboratory value was 0.920 +/- 0.259 (mean +/- SD), with a range from 0.708 to 1.202., Conclusion: The independent use of the AAPM/Sgouros method blood model approach to marrow dosimetry has brought these dose estimates to within 30% of the results obtained centrally compared with substantially higher uncertainties reported previously. Variations in calculation methodology or initial assumptions adopted by individual institutions may still contribute significant uncertainty to dose estimates, even when the same data are used as a starting point for the calculation comparison shown here. A clinically relevant, standard method for marrow dosimetry for radiolabeled antibodies is proposed as a benchmark for intercomparison purposes. A parameter sensitivity analysis and a summary discussion of the use of this model for potentially improving dose-response data correlation are also presented.

Placental transfer and fetal dose estimates have been published for women in early pregnancy and at the end of each trimester for a large number of radiopharmaceuticals. For the case of (18)F-FDG, a dose was given with no information about placental transfer of the radiopharmaceutical. Recent publications have reported quantitative values for maternal and fetal uptake of (18)F-FDG in primates and new values for (18)F-FDG kinetics. In this article, these data are applied to give radiation dose estimates for the fetus at all stages of pregnancy for (18)F-FDG. The recommended values are 2.2 x 10(-2) mGy/MBq in early pregnancy, 2.2 x 10(-2) mGy/MBq at 3-mo gestation, 1.7 x 10(-2) mGy/MBq at 6-mo gestation, and 1.7 x 10(-2) mGy/MBq at 9-mo gestation.

Unlabelled: Ibritumomab tiuxetan is an anti-CD20 murine IgG1 kappa monoclonal antibody (ibritumomab) conjugated to the linker-chelator tiuxetan, which securely chelates (111)In for imaging or dosimetry and (90)Y for radioimmunotherapy (RIT). Dosimetry and pharmacokinetic data from 4 clinical trials of (90)Y-ibritumomab tiuxetan RIT for relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) were combined and assessed for correlations with toxicity data., Methods: Data from 179 patients were available for analysis. Common eligibility criteria included <25% bone marrow involvement by NHL, no prior myeloablative therapy, and no prior RIT. The baseline platelet count was required to be > or = 100,000 cells/mm(3) for the reduced (90)Y-ibritumomab tiuxetan administered dose (7.4-11 MBq/kg [0.2-0.3 mCi/kg]) or > or = 150,000 cells/mm(3) for the standard (90)Y-ibritumomab tiuxetan administered dose (15 MBq/kg [0.4 mCi/kg]). Patients were given a tracer administered dose of 185 MBq (5 mCi) (111)In-ibritumomab tiuxetan on day 0, evaluated with dosimetry, and then a therapeutic administered dose of 7.4-15 MBq/kg (0.2-0.4 mCi/kg) (90)Y-ibritumomab tiuxetan on day 7. Both ibritumomab tiuxetan administered doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve ibritumomab tiuxetan biodistribution. Residence times for (90)Y in blood and major organs were estimated from (111)In biodistribution, and the MIRDOSE3 computer software program was used, with modifications to account for patient-specific organ masses, to calculate radiation absorbed doses to organs and red marrow., Results: Median radiation absorbed doses for (90)Y were 7.42 Gy to spleen, 4.50 Gy to liver, 2.11 Gy to lung, 0.23 Gy to kidney, 0.62 Gy (blood-derived method) and 0.97 Gy (sacral image-derived method) to red marrow, and 0.57 Gy to total body. The median effective blood half-life was 27 h, and the area under the curve (AUC) was 25 h. No patient failed to meet protocol-defined dosimetry safety criteria and all patients were eligible for treatment. Observed toxicity was primarily hematologic, transient, and reversible. Hematologic toxicity did not correlate with estimates of red marrow radiation absorbed dose, total-body radiation absorbed dose, blood effective half-life, or blood AUC., Conclusion: Relapsed or refractory NHL in patients with adequate bone marrow reserve and <25% bone marrow involvement by NHL can be treated safely with (90)Y-ibritumomab tiuxetan RIT on the basis of a fixed, weight-adjusted dosing schedule. Dosimetry and pharmacokinetic results do not correlate with toxicity.