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A first-in-human phase 1 clinical study was performed on 12 healthy adults with a high-specific-activity carrier-free formulation of 123I-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 123I-iobenguane showed organ distribution and whole-body retention similar to those of conventional 123I-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 123I-iobenguane.

Introduction Since the prostate-specific membrane antigen (PSMA) is frequently over-expressed in prostate cancer (PCa) several PSMA-targeting molecules are under development to detect and treat metastatic castration resistant prostate cancer (mCRPC). We investigated the tissue kinetics of a small molecule inhibitor of PSMA ((S)-2-(3-((S)-1-carboxy-5-(3-(4-[124I]iodophenyl)ureido)pentyl)ureido)pentanedioicacid; MIP-1095) using PET/CT to estimate radiation dosimetry for the potential therapeutic use of 131I-MIP-1095 in men with mCRPC. We also report preliminary safety and efficacy of the first 28 consecutive patients treated under a compassionate-use protocol with a single cycle of 131I-MIP-1095. Methods Sixteen patients with known prostate cancer underwent PET/CT imaging after i.v. administration of 124I-MIP-1095 (mean activity: 67.4 MBq). Each patient was scanned using PET/CT up to five times at 1, 4, 24, 48 and 72 h post injection. Volumes of interest were defined for tumor lesions and normal organs at each time point followed by dose calculations using the OLINDA/EXM software. Twenty-eight men with mCRPC were treated with a single cycle of 131I-MIP-1095 (mean activity: 4.8 GBq, range 2 to 7.2 GBq) and followed for safety and efficacy. Baseline and follow up examinations included a complete blood count, liver and kidney function tests, and measurement of serum PSA. Results I-124-MIP-1095 PET/CT images showed excellent tumor uptake and moderate uptake in liver, proximal intestine and within a few hours post-injection also in the kidneys. High uptake values were observed only in salivary and lacrimal glands. Dosimetry estimates for I-131-MIP-1095 revealed that the highest absorbed doses were delivered to the salivary glands (3.8 mSv/MBq, liver (1.7 mSv/MBq) and kidneys (1.4 mSv/MBq). The absorbed dose calculated for the red marrow was 0.37 mSv/MBq. PSA values decreased by >50 % in 60.7 % of the men treated. Of men with bone pain, 84.6 % showed complete or moderate reduction in pain. Hematological toxicities were mild. Of men treated, 25 % had a transient slight to moderate dry mouth. No adverse effects on renal function were observed. Conclusion Based on the biodistribution and dose calculations of the PSMA-targeted small molecule 124I-MIP-1095 therapy with the authentic analog 131I-MIP-1095 enables a targeted tumor therapy with unprecedented doses delivered to the tumor lesions. Involved lymph node and bone metastases were exposed to estimated absorbed doses upwards of 300 Gy. Electronic supplementary material The online version of this article (doi:10.1007/s00259-014-2713-y) contains supplementary material, which is available to authorized users.

2-((2S,5R,8S,11S)-5-benzyl-8-(4-((2S,3R,4R,5R,6S)-6-((2-(4-(3-18F-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 (18F-RGD-K5) has been developed as an αvβ3 integrin marker for PET. The purpose of this study was to determine the biodistribution and estimate the radiation dose from 18F-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 18F-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 18F-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:18F-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 18F-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 18F-RGD-K5 in monkeys and humans was similar, with increased uptake in the bladder, liver, and kidneys. There was rapid clearance of 18F-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. 18F-RGD-K5 can be used safely for imaging αvβ3 integrin expression in humans.

The primary purpose of this study was to assess the biodistribution and radiation dose resulting from administration of (18)F-EF5, a lipophilic 2-nitroimidazole hypoxia marker in ten cancer patients. For three of these patients (with glioblastoma) unlabeled EF5 was additionally administered to allow the comparative assessment of (18)F-EF5 tumor uptake with EF5 binding, the latter measured in tumor biopsies by fluorescent anti-EF5 monoclonal antibodies.(18)F-EF5 was synthesized by electrophilic addition of (18)F(2) gas, made by deuteron bombardment of a neon/fluorine mixture in a high-pressure gas target, to an allyl precursor in trifluoroacetic acid at 0° then purified and administered by intravenous bolus. Three whole-body images were collected for each of ten patients using an Allegro (Philips) scanner. Gamma counts were determined in blood, drawn during each image, and urine, pooled as a single sample. PET images were analyzed to determine radiotracer uptake in several tissues and the resulting radiation dose calculated using OLINDA software and standard phantom. For three patients, 21 mg/kg unlabeled EF5 was administered after the PET scans, and tissue samples obtained the next day at surgery to determine EF5 binding using immunohistochemistry techniques (IHC).EF5 distributes evenly throughout soft tissue within minutes of injection. Its concentration in blood over the typical time frame of the study (∼3.5 h) was nearly constant, consistent with a previously determined EF5 plasma half-life of ∼13 h. Elimination was primarily via urine and bile. Radiation exposure from labeled EF5 is similar to other (18)F-labeled imaging agents (e.g., FDG and FMISO). In a de novo glioblastoma multiforme patient, focal uptake of (18)F-EF5 was confirmed by IHC.These results confirm predictions of biodistribution and safety based on EF5's characteristics (high biological stability, high lipophilicity). EF5 is a novel hypoxia marker with unique pharmacological characteristics allowing both noninvasive and invasive measurements.

This is a first of many phase 1 study of Ultratrace Iobenguane I-131 (Ultratrace 131I-MIBG; Molecular Insight Pharmaceuticals, Inc., Cambridge, MA). High-specific-activity Ultratrace 131I-MIBG may provide improved efficacy and tolerability over carrier-added 131I-MIBG. We investigated the pharmacokinetics (PK), radiation dosimetry, and clinical safety in 11 patients with confirmed pheochromocytoma/paraganglioma (Pheo) or carcinoid tumors. A single 5.0-mCi (185 MBq) injection of Ultratrace 131I-MIBG, supplemented with 185 microg of unlabeled MIBG to simulate the amount of MIBG anticipated in a therapeutic dose, was administered. Over 120 hours postdose, blood and urine were collected for PK, and sequential whole-body planar imaging was performed. Patients were followed for adverse events for 2 weeks. Ultratrace 131I-MIBG is rapidly cleared from the blood and excreted in urine (80.3% +/- 2.8% of dose at 120 hours). For a therapeutic administration of 500 mCi (18.5 GBq), our estimate of the projected dose is 1.4 Gy for marrow and 10.4 Gy for kidneys. Safety results showed 12 mild adverse events, all considered unrelated to study drug, in 8 of 11 patients. These findings support the further development of Ultratrace 131I-MIBG for the treatment of neuroendocrine tumors, such as metastatic Pheo and carcinoid.

Temporary, low dose rate brachytherapy to the margins of resected brain tumors, using a balloon catheter system (GliaSite Radiation Therapy System) and liquid I-125 radiation source (Iotrex), began in 2002 at the University of Arizona Medical Center. Initially, all patients were treated on an inpatient basis. For patient convenience, we converted to outpatient therapy. In this article we review the exposure data and safety history for the 37 patients treated as outpatients. Proper patient selection and instruction is crucial to having a successful outpatient brachytherapy program. A set of evaluation criteria and patient instructions were developed in compliance with the U.S. Nuclear Regulatory Commission's document NUREG-1556 Volume 9 (Appendix U) and Arizona State Nuclear regulatory guidelines, which specify acceptable exposure rates for outpatient release in this setting. Of the 37 patients monitored, 26 patients were treated for recurrent glioblastoma multiforme (GBM), six for primary GBM, and five for metastatic brain tumors. All 37 patients and their primary caregivers gave signed agreement to follow a specific set of instructions and were released for the duration of brachytherapy (3-7 days). The typical prescription dose was 60 Gy delivered at 0.5 cm from the balloon surface. Afterloaded activities in these patients ranged from 90.9 to 750.0 mCi and measured exposure rates at 1 m from the head were less than 14 mR/h. The mean exposure to the caretaker measured by personal radiation Landauer Luxel + whole body dosimeters for 25 caretakers was found to be 9.6 mR, which was significantly less than the mean calculated exposure of 136.8 mR. For properly selected patients, outpatient brachytherapy is simple and can be performed within established regulatory guidelines.

(S,S)-[(18)F]FMeNER-D(2) is a recently developed positron-emission tomography (PET) radioligand for in vivo quantification of the norepinephrine transporter system. The aim of this study was to provide dosimetry estimates for (S,S)-[(18)F]FMeNER-D(2) based on human whole-body PET measurements.PET scans were performed for a total of 6.4 h after the injection of 168.9 +/- 31.5 MBq of (S,S)-[(18)F]FMeNER-D(2) in four healthy male subjects. Volumes of interest were drawn on the coronal images. Estimates of the absorbed dose of radiation were calculated using the OLINDA software.Uptake was largest in lungs, followed by liver, bladder, brain and other organs. Peak values of the percent injected dose (%ID) at a time after radioligand injection were calculated for the lung (21.6%ID at 0.3 h), liver (5.1%ID at 0.3 h), bladder (12.2%ID at 6 h) and brain (2.3%ID at 0.3 h). The largest absorbed dose was found in the urinary bladder wall (0.039 mGy/MBq). The calculated effective dose was 0.017 mSv/MBq.Based on the distribution and dose estimates, the estimated radiation burden of (S,S)-[(18)F]FMeNER-D(2) is lower than that of [(18)F]FDG. The radioligand would allow multiple PET examinations in the same research subject per year.

Object. The objectives of this study were to evaluate the safety and performance of a new brachytherapy applicator in the treatment of resected brain tumors in a canine model. Methods. The brachytherapy applicator is an inflatable balloon catheter that is implanted in the resection cavity remaining after a brain tumor has been debulked. After implantation the balloon is inflated with Iotrex, a sterile solution containing organically bound iodine-125. The low-energy photons emitted by the iodine-125 deposit a therapeutic radiation dose across short distances from the surface of the balloon. After delivery of a prescribed radiation dose to the targeted volume, the radioactive fluid is retrieved and the catheter removed. Small resections of the right frontal lobe were performed in large dogs. Magnetic resonance (MR) images were obtained and used to assess tissue response and to measure the conformance between the resection cavity wall and the balloon surface. In four animals a dose ranging from 36 to 59 Gy was delivered. Neurological status and histological characteristics of the brain were assessed in all dogs. Implantation and explantation as well as inflation and deflation of the device were easily accomplished and well tolerated. The device was easily visualized on MR images, which demonstrated the expected postsurgical changes. The resection cavity and the balloon were highly conformal (range 93–100%). Histological changes to the cavity margin were consistent with those associated with surgical trauma. Additionally, radiation-related changes were observed at the margins of the resection cavity in dogs in which the brain was irradiated. Conclusions. This balloon catheter and 125I radiotherapy solution system can safely and reliably deliver radiation to the margins of brain cavities created by tumor resection. Results of this study showed that intracranial pressure changes due to balloon inflation and deflation were unremarkable and characteristic of the imaging properties and radiation safety profile of the device prior to its clinical evaluation. Clinically relevant brachytherapy (adequate target volume and total dose) was accomplished in all four animals subjected to treatment.

Prostate-specific membrane antigen (PSMA) is a well-established target for developing radiopharmaceuticals for imaging and therapy of prostate cancer (PCa). We have recently reported that novel 99m Tc-labeled small-molecule PSMA inhibitors bind with high affinity to PSMA-positive tumor cells in vitro and localize in PCa xenografts. This study reports the first, to our knowledge, human data in men with metastatic PCa and in healthy male subjects. Methods: Under an exploratory investigational new drug, using a cross-over design, we compared the pharmacokinetics, biodistribution, and tumor uptake of 99m Tc-MIP-1404 and 99m Tc-MIP-1405 in 6 healthy men and 6 men with radiographic evidence of metastatic PCa. Wholebody images were obtained at 10 min and 1, 2, 4, and 24 h. SPECT was performed between 3 and 4 h after injection. Results: Both agents cleared the blood rapidly, with MIP-1404 demonstrating significantly lower urinary activity (7%) than MIP-1405 (26%). Both agents showed persistent uptake in the salivary, lacrimal, and parotid glands. Uptake in the liver and kidney was acceptable for imaging at 1–2 h. In men with PCa, both agents rapidly localized in bone and lymph node lesions as early as 1 h. SPECT demonstrated excellent lesion contrast. Good correlation was seen with bone scanning; however, more lesions were demonstrated with 99mTc-MIP-1404 and 99mTc-MIP-1405. The high-contrast images exhibited tumor-tobackground ratios from 3:1 to 9:1 at 4 and 20 h. Conclusion: Compared with the standard-of-care bone scanning, 99mTc-MIP1404 and 99mTc-MIP-1405 identified most bone metastatic lesions and rapidly detected soft-tissue PCa lesions including subcentimeter lymph nodes. Because 99mTc-MIP-1404 has minimal activity in the bladder, further work is planned to correlate imaging findings with histopathology in patients with high-risk metastatic PCa.

This paper compares experimentally measured and calculated dose-rate distributions for a novel 125 I liquid-filled brachytherapy balloon applicator (the GliaSite RTS), designed for the treatment of malignant brain-tumor resection-cavity margins. This work is intended to comply with the American Association of Physicists in Medicine (AAPM) Radiation Therapy Committee’s recommendations [Med. Phys. 25, 2269–2270 (1998)] for dosimetric characterization of low-energy photon interstitial brachytherapy sources. Absolute low dose-rate radiochromic film (RCF) dosimetry measurements were performed in coronal planes about the applicator. The applicator was placed in a solid water phantom, machined to conform to the inflated applicator’s surface. The results were used to validate the accuracy of Monte Carlophoton transport (MCPT) simulations and a point-source dose-kernel algorithm in predicting dose to water. The absolute activity of the 125 I solution was determined by intercomparing a National Institute of Standards and Technology (NIST) 125 I standard with a known mass of radiotherapy solution (Iotrex™) in an identical vial and geometry. For the two films not in contact with applicator, the average agreement between RCF and MCPT (specified as the mean absolute deviation in successive 4 mm rings) was found to be within ±5% at distances 0.2–25 mm from the film centers. For the two films touching the catheter, the mean agreement was ±14.5% and 7.5% near the balloon surface but improving to 7.5% and 6% by 3.5 mm from the surface. These errors, as large as 20% in isolated pixels, are likely due to trim damage, 125 I contamination, and poor conformance with the balloon. At larger distances where the radiationdoses were very low, the observed discrepancies were significantly larger than expected. We hypothesize that they are due to a dose-rate dependence of the RCF response. A 1%–10% average difference between a simple one-dimensional path-length semiempiricaldose-kernel model and the MCPT calculations was observed over clinically relevant distances.

Iotrex is an aqueous radiotherapy solution containing sodium 3-(125I)iodo-4-hydroxybenzenesulfonate (125I-HBS), which is used as the radiation source for the brachytherapy of resected of brain tumor cavity margins with the GliaSite catheter. During routine clinical use of this brachytherapy applicator and radiation source, approximately 0.1% of the afterloaded Iotrex will diffuse through the GliaSite balloon. Our purpose was to assess the radiation doses to normal organs under routine clinical use of the GliaSite.Five groups of rats received intracerebral injections of an 131I-HBS solution (131I used as a surrogate for 125I in the synthesis of 125I-HBS) with one group sacrificed at 15 minutes, 30 minutes, 1 hour, 2 hours and 4 hours post-administration. Urine was collected and activity retention in numerous organs was measured. The biodistribution data were used to estimate radiation doses to normal organs of the Reference Adult Male and Female phantoms.Radioactivity was rapidly and completely cleared from the brain (98% cleared by 2 hours) and total body (urinary clearance; 93%@2 hours). No organ retained0.7% of the radioactivity at 4 hours. For 100% loss of the radiotherapy solution from the balloon catheter (device failure), all organs would receive less than 100 mGy (10 rad), except the bladder wall (2800 mGy, 280 rad), uterus (130 mGy, 13 rad) and distal colon (270 mGy, 27 rad). Under normal conditions, all organ doses are 1000-fold lower (3 mGy or 0.3 rad).Under routine clinical conditions, the radiation doses to normal organs are inconsequential. Should the maximum clinical load of Iotrex (16.7 GBq of 125I) be released intracerebrally, the radiation doses to all organs would be below the thresholds for deterministic effects.

Purpose: This paper characterizes the dosimetric properties of a novel balloon brachytherapy applicator for the treatment of the tissue surrounding the resection cavity of a malignant brain tumor. Methods and Materials: The applicator consists of an inflatable silicone balloon reservoir attached to a positionable catheter that is intraoperatively implanted into the resection cavity and postoperatively filled with a liquid radionuclide solution. A simple dosimetric model, valid in homogeneous media and based on results from Monte Carlo photon-transport simulations, was used to determine the dosimetric characteristics of spherical geometry balloons filled with photon-emitting radionuclide solutions. Fractional depth-dose (FDD) profiles, along with activity densities, and total activities needed to achieve specified dose rates were studied as a function of photon energy and source-containment geometry. Dose–volume histograms (DVHs) were calculated to compare idealized balloon-applicator treatments to conventional 125 I seed volume implants. Results: For achievable activity densities and total activities, classical low dose rate (LDR) treatments of residual disease at distances of up to 1 cm from the resection cavity wall are possible with balloon applicators having radii between 0.5 cm and 2.5 cm. The dose penetration of these applicators increases approximately linearly with balloon radius. The FDD profile can be made significantly more or less penetrating by combining selection of radionuclide with source-geometry manipulation. Comparisons with 125 I seed-implant DVHs show that the applicator can provide a more conformal therapy with no target tissue underdosing, less target tissue overdosing, and no healthy tissue "hot spots;" however, more healthy tissue volume receives a dose of the prescribed dosage or less. Conclusions: This device, when filled with 125 I solution, is suitable for classical LDR treatments and may be preferable to 125 I interstitial-seed implants in several respects. Manipulation of the dosimetric properties of the device can improve its characteristics for brain tumor treatment and may make it suitable for boosting the lumpectomy margins in conservative breast cancer treatment.

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. 123I-MIP-1072 was also studied in 6 healthy volunteers. Whole-body planar and SPECT/CT imaging was performed and pharmacokinetics studied over 2– 3d . Target-to-background ratios were calculated. Absorbed radiation doses were estimated using OLINDA/EXM. Results: 123I-MIP1072 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-MIP1095, respectively. Conclusion: 123I-MIP-1072 and 123I-MIP1095 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.

The research discussed in this article aimed to characterize better the biodistribution, excretion and radiation dosimetry of the single photon emission computed tomography (SPECT) D 2 Dopamine receptor radioligand [ 123 I]IBF. Following administration of 111 ± 12 MBq [ 123 I]IBF, seven healthy human subjects were scanned serially with a whole body imager over a 48-h period. Transmission images were obtained with a scanning line source for attenuation correction of the emission images. Urine was collected for 48 h to measure the fraction of activity voided by the renal system. Radiation absorbed dose estimates were performed using biokinetic modeling and the Medical Internal Radiation Dose (MIRD) schema. Highest absorbed doses were to the kidney (0.13 ± 0.02 mGy/MBq) and urinary bladder wall (0.11 ± 0.01 mGy/ MBq). The effective dose equivalent was 0.041 ± 0.005 mSv/MBq. Peak brain uptake represented 8% of the injected activity. Rapid urinary excretion minimized the absorbed dose to most tissues. The mean cumulative urinary excretion fraction was 69%. Thus [ 123 I]IBF is a promising SPECT agent for imaging the D 2 dopamine receptor in humans with high brain uptake and favorable dosimetry.

The central benzodiazepine receptor tracer [ N -methyl- 11 C]iomazenil (Ro 16-0154) was synthesized by alkylation of the desmethyl precursor noriomazenil with [ 11 C]methyl iodide. The [ 11 C]CH 3 I (prepared by reduction of [ 11 C]CO 2 with LiAlH 4 followed by reaction with HI) was reacted with noriomazenil in N,N -dimethylformamide and Bu 4 N + OH − for 1 min at 80 °C and purified by HPLC (C 18 , 34% CH 3 CN/H 2 O, 7 mL/min). The product was obtained with synthesis time 35 ± 5 min (mean ± SD, n = 7), radiochemical yield (EOB) 36 ± 16%, radiochemical purity 99 ± 1%, and specific activity 5100 ± 2800 mCi/μmol. Absorbed radiation doses were calculated from previously acquired human biodistribution data. The urinary bladder wall received the highest dose (0.099 mGy/MBq) for 4.8 h voiding interval and the effective dose equivalent was 0.015 mSv/MBq. After i.v. injection of [ 11 C]iomazenil in an adult baboon or healthy human volunteer, radioactivity accumulated in the cortex with time-activity curves in agreement with results obtained with [ 11 C]flumazenil PET and [ 123 I]iomazenil SPECT studies. The count rate was sufficient to obtain quantitative images up to 2 h post-injection with a 14mCi injection. These results suggest that [ 11 C]iomazenil will be a useful agent for measuring benzodiazepine receptors in vivo by positron emission tomography.

Transferrin, when injected intracranially into glioblastoma multiforme lesions, acts as a cytotoxic substance. Transferrin, radiolabeled with In-111, can be coinjected and subsequent scintigraphic imaging can demonstrate the biokinetics of the cytotoxic transferrin. The administration of 111In transferrin into a brain tumor results in distribution of radioactivity in the brain, brain tumor, and the cerebrospinal fluid (CSF). Information about absorbed radiation doses to these regions, as well as other nearby tissues and organs, is important for evaluating radiation-related risks from this procedure. The radiation dose is usually estimated for a mathematical representation of the human body. We have included source/target regions for the eye, lens of the eye, spinal column, spinal CSF, cranial CSF, and a 100-g tumor within the brain of an adult male phantom developed by Cristy and Eckerman. The mathematical models of the spinal column, spinal CSF, and the eyes were developed previously, however, these source/targets have not been routinely included in photon transport simulations. Specific absorbed fractions (SAFs) as a function of photon energy were calculated using the ALGAMP computer code, which utilizes Monte Carlo techniques for simulating photon transport. The ALGAMP code was run three times, with the source activity distributed uniformly within the tumor, cranial CSF, and the spinal CSF volumes. These SAFs, which were generated for 12 discrete photon energies ranging from 0.01 to 4.0 MeV, were used with decay scheme data to calculate S-values needed for estimating absorbed doses. S-values for 111In are given for three source regions (brain tumor, cranial CSF, and spinal CSF) and all standard target regions/organs, the eye and lens, as well as to tissues within these source regions. S-values for the skeletal regions containing active marrow are estimated. These results are useful in evaluating the radiation doses from intracranial administration of 111In transferrin. The SAFs are also generally useful for calculation of absorbed dose from any radionuclide in these source regions.

131I-metaiodobenzylguanidine (MIBG) is specifically taken up in neuroblastoma, with a response rate of 20%–37% in relapsed disease. Nonradioactive carrier MIBG molecules inhibit uptake of 131I-MIBG, theoretically resulting in less tumor radiation and increased risk of cardiovascular toxicity. Our aim was to establish the maximum tolerated dose of no-carrier-added (NCA) 131I-MIBG, with secondary aims of assessing tumor and organ dosimetry and overall response. Methods: Eligible patients were 1–30 y old with resistant neuroblastoma, 131I-MIBG uptake, and cryopreserved hematopoietic stem cells. A diagnostic dose of NCA 131I-MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. The treatment dose of NCA 131I-MIBG (specific activity, 165 MBq/μg) was adjusted as necessary on the basis of critical organ tolerance limits. Autologous hematopoietic stem cells were infused 14 d after therapy to abrogate prolonged myelosuppression. Response and toxicity were evaluated on day 60. The NCA 131I-MIBG was escalated from 444 to 777 MBq/kg (12–21 mCi/kg) using a 3 + 3 design. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/μL within 28 d or platelets to greater than 20,000/μL within 56 d, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions. Results: Three patients each were evaluable at 444, 555, and 666 MBq/kg without DLT. The dose of 777 MBq/kg dose was not feasible because of organ dosimetry limits; however, 3 assigned patients were evaluable for a received dose of 666 MBq/kg, providing a total of 6 patients evaluable for toxicity at 666 MBq/kg without DLT. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight patients had 13 soft-tissue lesions with tumor-absorbed doses of 26–378 Gy. Four of 15 patients had a complete (n = 1) or partial (n = 3) response, 1 had a mixed response, 4 had stable disease, and 6 had progressive disease. Conclusion: NCA 131I-MIBG with autologous peripheral blood stem cell transplantation is feasible at 666 MBq/kg without significant nonhematologic toxicity and with promising activity.

The distribution of the central benzodiazepine receptor specific ligand iodine-123 iomazenil was investigated in seven human adults from whole-body scans, blood samples and urine collected up to 24 h after injection. Using 12 source organs, the MIRD method was applied to calculate the absorbed radiation dose of the radioligand in various organs. The urinary bladder wall (0.15 mGy/MBq), lower large intestinal wall (0.071 mGy/MBq) testes (0.044 mGy/MBq) and upper large intestined wall (0.038 mGy/MBq) received the highest absorbed doses. The average effective dose equivalent of 123I-IBZM for adults was estimated to be 0.033 mSv/MBq.

F-HX4 is a novel positron emission tomography (PET) tracer for imaging hypoxia. The purpose of this study was to determine the biodistribution and estimate the radiation dose of F-HX4 using whole-body PET/computed tomography (CT) scans in monkeys and humans.Successive whole-body PET/CT scans were done after the injection of F-HX4 in four healthy humans (422±142 MBq) and in three rhesus monkeys (189±3 MBq). Biodistribution was determined from PET images and organ doses were estimated using OLINDA/EXM software.The bladder, liver, and kidneys showed the highest percentage of the injected radioactivity for humans and monkeys. For humans, approximately 45% of the activity is eliminated by bladder voiding in 3.6 h, and for monkeys 60% is in the bladder content after 3 h. The critical organ is the urinary bladder wall with the highest absorbed radiation dose of 415±18 (monkeys) and 299±38 μGy/MBq (humans), in the 4.8-h bladder voiding interval model. The average value of effective dose for the adult male was estimated at 42±4.2 μSv/MBq from monkey data and 27±2 μSv/MBq from human data.Bladder, kidneys, and liver have the highest uptake of injected F-HX4 activity for both monkeys and humans. The urinary bladder wall receives the highest dose of F-HX4 and is the critical organ. Thus, patients should be encouraged to maintain adequate hydration and void frequently. The effective dose of F-HX4 is comparable with that of other F-based imaging agents.

Radiolabeled benzamides are attractive candidates for targeted radiotherapy of metastatic melanoma as they bind melanin and exhibit high tumor uptake and retention. One such benzamide, N-(2-diethylamino-ethyl)-4-(4-fluoro-benzamido)-5-iodo-2-methoxy-benzamide (MIP-1145), was evaluated for its ability to distinguish melanin-expressing from amelanotic human melanoma cells, and to specifically localize to melanin-containing tumor xenografts. The binding of [131I]MIP-1145 to melanoma cells in vitro was melanin dependent, increased over time, and insensitive to mild acid treatment, indicating that it was retained within cells. Cold carrier MIP-1145 did not reduce the binding, consistent with the high capacity of melanin binding of benzamides. In human melanoma xenografts, [131I]MIP-1145 exhibited diffuse tissue distribution and washout from all tissues except melanin-expressing tumors. Tumor uptake of 8.82% injected dose per gram (ID/g) was seen at 4 hours postinjection and remained at 5.91% ID/g at 24 hours, with tumor/blood ratios of 25.2 and 197, respectively. Single photon emission computed tomography imaging was consistent with tissue distribution results. The administration of [131I]MIP-1145 at 25 MBq or 2.5 GBq/m2 in single or multiple doses significantly reduced SK-MEL-3 tumor growth, with multiple doses resulting in tumor regression and a durable response for over 125 days. To estimate human dosimetry, gamma camera imaging and pharmacokinetic analysis was performed in cynomolgus monkeys. The melanin-specific binding of [131I]MIP-1145 combined with prolonged tumor retention, the ability to significantly inhibit tumor growth, and acceptable projected human dosimetry suggest that it may be effective as a radiotherapeutic pharmaceutical for treating patients with metastatic malignant melanoma. Cancer Res; 70(10); 4045–53. ©2010 AACR.

Numerous improvements in the understanding of the biology of primary brain tumors have been reported. The resultant application of this information to the therapy of these lesions offers promising alternatives. For any of a number of reasons delivery of these therapies to the target neoplasm can be challenging. Convection enhanced delivery has been established as a modality that has been shown to circumvent some of the impediments to treatment agent delivery. This report described the preliminary preclinical use of a balloon tipped catheter with a channel built in for infusion of therapy directly into the brain. A series of 10 canines were studied using bolus and continuous infusions with the balloon either inflated or deflated. The infusates contained gadolinium to allow imaging of the convection process. The character of the cerebral penetration is described ranging from minimal cerebral penetration with uninflated balloons used with bolus injections to extensive bilateral penetration using inflated balloons and continuous infusions. This data demonstrates the feasibility and potential value of such a system and warrants a more detailed analysis of the device using a wider variety of infusion parameters, assessment of larger infusate molecule sizes likely to be solely dependent on convection and direct comparison to standard catheter convection techniques.

(S,S)-[F]FMeNER-D2 is a recently developed norepinephrine transporter ligand which is a potentially useful radiotracer for mapping the brain and heart norepinephrine transporter in vivo using positron emission tomography. In this work, we quantified the biodistribution over time and radiation exposure to multiple organs with (S,S)-[F]FMeNER-D2.Whole-body images were acquired for 21 time points in two cynomolgus monkeys for approximately 270 min after injection of radioligand. Compressed 3-D to 2-D planar images were used to identify organs with the highest radiation exposure at each time point. Estimates of the absorbed dose of radiation were calculated using the MIRDOSE 3.1 software program performed with the dynamic bladder and ICRP 30 gastrointestinal tract models.In planar images, peak values of the percent injected dose (%ID) at a time after radioligand injection were calculated for the lungs (26.76% ID at 1.42 min), kidneys (13.55% ID at 2.18 min), whole brain (5.65% ID at 4.48 min), liver (7.20% ID at 2 min), red bone marrow (5.02% ID at 2.06 min), heart (2.36% ID at 1.42 min) and urinary bladder (23% ID at 250 min). Assuming a urine voiding interval of 2.4 h, the four organs with highest exposures in microGy . MBq ( mrad . mCi) were kidneys 126 (468), heart wall 108 (399), lungs 88.4 (327) and urinary bladder 114 (422). The effective doses were estimated with and without urine voiding at a range of 123 (33) and to 131 (35.5) microGy . MBq ( mrad . mCi).The estimated radiation burden of (S,S)-[F]FMeNER-D2 is comparable to that of other F radioligands.

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.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.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.(123)I-ADAM may be a safe and effective radiotracer for imaging serotonin transporters in the brain and the body.

81 Background: Oncoplastic surgery (OPS) has improved outcomes for partial mastectomy. However, tissue rearrangement poses challenges in the post-operative management of these patients. In most cases, these patients will require post-operative radiotherapy. Accurately visualizing the surgical cavity can be particularly troublesome in patients who have oncoplastic closure of the resection cavity. Recent advances have made it feasible to perform external beam radiation using advanced methods, but these are not commonly used for breast cancer. This is due to the difficulty in identifying the exact area of the surgical site. In this series of patients, a novel method for marking the surgical site when using oncoplastic techniques was evaluated. Methods: 65 patients had a 3-D tissue marker implanted at the time of lumpectomy. All patients were candidates for partial mastectomy and local breast reconstruction using OPS. Post-operative treatment plans for radiation and/or adjuvant chemotherapy were completed. Patients were evaluated with standard breast imaging methods for treatment planning. Results: The marker was easily identified and clearly delineated within the lumpectomy cavity. It provided 3-D characterization of the borders surrounding the cavity, and was easily distinguished from seroma and other tissue changes. Respiratory motion was easily tracked using the device making it possible to use IMRT and accelerated protocols. Use of the marker resulted in treatment volumes that were reduced by an average of 50% when compared to standard methods. In appropriate patients when the marker facilitated an accelerated protocol, total treatment time was decreased to 5-7 days. No complications were reported, and overall patient outcomes were excellent. Conclusions: This novel 3-D marker was consistently visualized without difficulty, was readily incorporated into standard practices and had appreciable benefits when designing optimal treatment plans. Its unique features were helpful in all cases, but particularly useful when using oncoplastic techniques to reconstruct the breast with local tissue flaps.

Tables of radiation dose estimates based on the Cristy-Eckerman adult male phantom are provided for a number of radiopharmaceuticals commonly used in nuclear medicine. Radiation dose estimates are listed for all major source organs, and several other organs of interest. The dose estimates were calculated using the MIRD Technique as implemented in the MIRDOSE3 computer code, developed by the Oak Ridge Institute for Science and Education, Radiation Internal Dose Information Center. In this code, residence times for source organs are used with decay data from the MIRD Radionuclide Data and Decay Schemes to produce estimates of radiation dose to organs of standardized phantoms representing individuals of different ages. The adult male phantom of the Cristy-Eckerman phantom series is different from the MIRD 5, or Reference Man phantom in several aspects, the most important of which is the difference in the masses and absorbed fractions for the active (red) marrow. The absorbed fractions for flow energy photons striking the marrow are also different. Other minor differences exist, but are not likely to significantly affect dose estimates calculated with the two phantoms. Assumptions which support each of the dose estimates appears at the bottom of the table of estimates for a given radiopharmaceutical. In most cases, the model kinetics or organ residence times are explicitly given. The results presented here can easily be extended to include other radiopharmaceuticals or phantoms.

IPCIT [2 beta-carboisopropoxy-3 beta-(4-iodophenyl)tropane; also designated RTI-121] is the isopropyl ester of beta-CIT [2 beta-carbomethoxy-3 beta-(4-iodophenyl) tropane]. Although beta-CIT binds to dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transporters, IPCIT has been reported to be selective for the DA transporter. IPCIT was labeled with 125I and its receptor binding to membranes prepared from baboon striatum was compared with that of [125I] beta-CIT. These studies confirmed the relative selectivity of IPCIT for the DA transporter in comparison to 5-HT and NE transporters. The nonspecific binding of [125I]IPCIT was almost four times greater than that of [125I] beta-CIT. The biodistribution of IPCIT was examined in two baboons with whole body imaging for 24-30 h after administration of 3 mCi of 123I-labeled tracer. The brain uptake peaked within the first hour at 9.2% of the injected dose and the majority of activity in the body cleared through the hepatobiliary system. The distribution of activity within the brain was examined with ex vivo autoradiography in one monkey injected with [123I]IPCIT. Activity was concentrated in the caudate and putamen and had values of 5 and 7 microCi/cm3 per microCi/g, respectively. The distribution in brain regions receiving moderately dense serotonergic innervation (e.g. superior colliculus and thalamus) had levels of activity equivalent to that in cerebellum. This study confirmed the in vitro and in vivo selectivity of IPCIT for the DA transporter but also showed that [125I]IPCIT had higher in vitro nonspecific binding than [125I] beta-CIT.

9512 Background: 131I-MIBG is specifically taken up in neuroblastoma, with a response rate >30% in relapsed disease. The presence of non-radioactive “carrier” MIBG molecules increases risk of cardiovascular side effects and can inhibit tumor uptake of 131I-MIBG, reducing tumor radiation. Our primary aim was to establish the maximum tolerated dose (MTD) of no-carrier-added MIBG with autologous hematopoietic stem cell (AHSC) support. Methods: Eligible patients were age 1-30 years with resistant neuroblastoma, MIBG avid tumors, and cryopreserved AHSC. The nca-MIBG therapeutic dose was escalated in 3 mCi/kg increments from 12-21 mCi/kg using a 3+3 design. The administered dose was limited by gamma image-derived pretreatment organ dosimetry and normal tissue tolerance estimates of Emami (1991). AHSC were infused 14 days post therapy. Response and toxicity were evaluated day 60. Dose limiting toxicity (DLT) was failure to engraft or grade 3 or 4 non-hematologic toxicity except grade 3 pre-defined exclusions. Re...

The correspondence between Drs. Macleod and Kemp [1] and Drs. Johansson et al. [2] in this issue is an example of the controversy that has arisen over use of the quantities effective dose equivalent (EDE) [3] and effective dose (E) [4]. Johansson et al. correctly point out the interpretations of these quantities, as well as their intended applications. The EDE was originally defined for use in radiation protection programs for situations in which nonstochastic effects do not occur. The adaptation to medical uses of radiation, including radiology and nuclear medicine, has been made by authors other than Johansson et al. [5, 6, 7] and advocated by the ICRP in ICRP Publication 53 [8]. Nonetheless, some people remain opposed to the use of the unit in medicine. The traditional approach to the characterization of radiation dosimetry in medical uses of radiation has been to report individual organ absorbed doses and a quantity called "total body" (or "whole body ") dose. Thus, radiation use committees, regulatory agencies, physicians, manufacturers, and others have become focused on calculation of "critical organ" dose and "total body" dose. As noted by Johansson et al., one accepted way to evaluate a patient's risk from stochastic effects would be to consider the average doses and radiation sensitivities of all organs. In principle, the EDE permits this evaluation to be made for different radiopharmaceuticals, as well as different modalities of ionizing radiation exposure, with the results being directly comparable. Furthermore, the EDE is designed to represent the uniform wholebody exposure that would carry the same risk as the actual nonuniform exposure received. The quantity "total body" dose, on the other hand, is usually calculated by dividing all of the energy absorbed in all tissues from a given exposure by the total body mass. This quantity is completely meaningless when a nonuniform distribution of radioactivity occurs. "Total body" dose is clearly inappropriate for evaluating the risk from nuclear medicine examinations and should not be the basis for decision-making or comparison of agents or procedures. The question becomes whether an effective dose equivalent or effective dose can be a suitable substitute for "total body" dose (or, more appropriately, "total body" dose equivalent). The effective dose contains by definition two sets of so-called "weighting factors," which are introduced through multiplication. The first are the "radiation weighting factors" (formerly quality factors), which express the relative effectiveness of different types of radiations at producing biological damage. Multiplication of a tissue absorbed dose (DT,R) (Gy, mGy, rad, etc.) by the appropriate radiation weighting factor (WR) (including all radiations) produces the tissue equivalent dose (HT) (formerly called dose equivalent) (Sv, mSv, rem, etc.)