Abstract Tin-117 m (117mSn) is used to treat dogs with osteoarthritic joints by radiosynoviorthesis. The internal conversion and Auger electrons emitted by the 117mSn provide the therapeutic effect. Sn-117 m also emits x rays and gamma rays, of which the most significant is 158.6 keV. Accurate information regarding the interactions of a person with a treated dog is needed to determine the person’s total dose and thus regulatory compliance; i.e., a time and motion study. Prior studies have characterized the radiation field emitted by a treated dog, determined the effective dose rates to a person based on those radiation fields, and evaluated dog-human interactions. These studies have been tied together to calculate the prospective dose to the owner of a treated dog. The behavior modifications needed to comply with public dose limits were identified, and a template for written instructions limiting dose was developed. Further calculations based on the written instructions were made to determine the necessary duration of the instructions. The result is guidance that may be used by veterinary practitioners to release treated dogs in accordance with the public dose limits.

Response inhibition and interference resolution are often considered subcomponents of an overarching inhibition system that utilizes the so-called cortico-basal-ganglia loop. Up until now, most previous functional magnetic resonance imaging (fMRI) literature has compared the two using between-subject designs, pooling data in the form of a meta-analysis or comparing different groups. Here, we investigate the overlap of activation patterns underlying response inhibition and interference resolution on a within-subject level, using ultra-high field MRI. In this model-based study, we furthered the functional analysis with cognitive modelling techniques to provide a more in-depth understanding of behaviour. We applied the stop-signal task and multi-source interference task to measure response inhibition and interference resolution, respectively. Our results lead us to conclude that these constructs are rooted in anatomically distinct brain areas and provide little evidence for spatial overlap. Across the two tasks, common BOLD responses were observed in the inferior frontal gyrus and anterior insula. Interference resolution relied more heavily on subcortical components, specifically nodes of the commonly referred to indirect and hyperdirect pathways, as well as the anterior cingulate cortex, and pre-supplementary motor area. Our data indicated that orbitofrontal cortex activation is specific to response inhibition. Our model-based approach provided evidence for the dissimilarity in behavioural dynamics between the two tasks. The current work exemplifies the importance of reducing inter-individual variance when comparing network patterns and the value of UHF-MRI for high resolution functional mapping.

Abstract Tin-117m (117mSn) is used to treated dogs with osteoarthritic joints by radiosynoviorthesis. The internal conversion and Auger electrons emitted by the 117mSn provide the therapeutic effect. Sn-117m also emits gamma rays, of which the most significant is 158.6 keV. The external radiation field around a treated dog is of interest to limit the dose to the owners/caretakers of the dog. The dog’s torso attenuates the radiation being emitted toward the opposite side of the dog’s body. This leads to a radiation field that is significantly non-isotropic. This study characterizes the anisotropy of this field to permit maximum dose rate measurements to be used to calculate the dose to individuals in the vicinity of the dog. Measurements were made in nine directions and at two distances, 0.3 and 1.0 m, to characterize common distances and spatial orientations for human-dog interactions. From these measurements, the percent reduction in the average dose rate compared to the maximum dose rate was determined. From a radiation safety perspective, the important factor is the minimum amount of shielding effectiveness or percent reduction that can be expected. A reasonable measure for this value is the fifth percentile of the shielding effectiveness distribution. The fifth percentile shielding effectiveness measures are 27% and 21% at 0.3 and 1.0 m, respectively.

Abstract The treatment of pets, service animals, and pre-clinical research subjects with radionuclides raises concern for the safety of the people who interact with the animals after their treatment. Three treatments of skeletal conditions in dogs are considered in this study: 153Sm-1,4,7,10-tetraazacylcododecanetetramethylenephosphonic acid, which is a bone-seeking radiopharmaceutical; unencapsulated 90Y permanent interstitial implants, which are sometimes called “liquid brachytherapy”; and 117mSn radiosynoviorthesis, which is also called radiosynovectomy. External exposure rate readings of the 153Sm and 117mSn treatments, and Monte Carlo simulations of 117mSn at a distance of 1 m and of all three in direct contact with tissue were analyzed for doses. Dogs that have received any of these treatments using typically administered activities may be released from radiation safety isolation immediately after treatment from the standpoint of external exposure. People should avoid prolonged close proximity, such as sleeping with a treated dog, for three weeks following an 90Y interstitial implant or for a month following 117mSn radiosynoviorthesis. No such avoidance is necessary after treatment with 153Sm-1,4,7,10-tetraazacylcododecanetetramethylenephosphonic acid.

1523 Objectives: Sn-117m is a unique isotope that emits both a gamma photon which is used in detection and imaging, as well as conversion electron (C.E.) energy that is being used experimentally to treat human inflammatory vascular diseases, and commercially to treat canine osteoarthritis. Methods are being developed for treating and imaging inflammatory conditions in ungulates, specifically the serious condition of equine laminitis that causes pathological changes in the hoof often leading to long lasting, crippling deterioration in function. The use of a radionuclide conjugate, such as Sn-117m attached or linked into a chelating agent and conjugated to a macrophage targeting agent such as annexin V, annexin A1, and T-DPA, is effective at decreasing macrophage mediated inflammation. A radionuclide conjugate is systemically administered for delivery to the hoof of an ungulate, binding to inflammatory cells of the hoof lamina and reversing the inflammatory destructive laminitis without affecting tissue adjacent to the area of interest. The radionuclide conjugate may include [Sn-117m]-DOTA-annexin V, [Sn-117m]-DOTA-[T-DPA], [Sn-117m]-DOTA-annexin A1 (lipocortin 1). Other chelating agents may be used in place of DOTA. Methods: The radionuclide conjugate is infused, such as with a direct arterial injection into the palmar distal artery or other vascular infusion methods, to target infiltrating macrophages that exacerbate the relentless inflammatory process underlying laminitis. Administering the radionuclide conjugate ameliorates the inflammatory cycle and allows the tissue to heal. Infusions of the radionuclide conjugate not only treat the afflicted area but also allow imaging of the laminitis due to the existence of the Sn-117m gamma photon. Imaging may be performed with a gamma camera or with single photon emission computerized tomography (SPECT). Annexin V is a naturally occurring human protein that binds to specific cell membrane chemicals that are expressed on macrophages that cause the inflammatory conditions in equine laminitis. When conjugated to Sn-117m, the resulting Sn-annexin molecule has been shown to specifically bind to inflammatory cells in human vulnerable plaque and has successfully localized to inflammatory fibrocalcific disease. We expect this conjugate to similarly bind to inflammatory cells in equine laminitis and induce apoptosis. Sn-annexin binds to the inflammatory cell outer membrane leaflet onto phosphatidylserine A. Results: Sn-117m was successfully conjugated to a targeting molecule that localizes to the outer cell membrane of inflammatory cells, resulting in the apoptotic death of these cells. Inflammation is considered a significant contributor to laminitis, especially at its onset. The systemic injection of our inflammation targeting agent [Sn-117m]-DOTA-annexin V has been studied in several animal models. Imaging of human pathologic inflammatory cell collections in vivo as well as animal therapeutic trials in inflammatory states suggest that [Sn-117m]-DOTA-annexin V may be used as a laminitis therapeutic agent. Conclusions: Equine laminitis is a crippling and costly disorder with inadequate therapy despite decades of extensive research. The etiologies of this condition are diverse but in many presentations of laminitis there appears to be an inflammatory component. The active therapeutic agent proposed in this overview is the unique C.E. energy emitted from the isotope Sn-117m. Sn-117m has been successfully chemically linked to an inflammatory cell targeting large molecule (i.e., annexin V) with statistically significant induction of macrophage apoptosis.

This longitudinal prospective exploratory study used serial measurements in five dogs to evaluate safety and retention of a tin-117 m (117m Sn) colloid after intra-articular injection in normal elbow joints. Each dog was deemed healthy based on physical examination, laboratory results, and radiographic evaluation of both elbows. While anesthetized, each received an MRI of both elbows, followed by fluorine-18 fluorodeoxyglucose positron emission tomography scans of both elbow joints and associated lymph nodes. Joint fluid (0.5-1.0 mL) was withdrawn aseptically from the left elbow joint, followed by intra-articular injection of 117m Sn colloid (92.5 MBq; 1-1.5 ml). Post-injection assessments included blood counts, serum chemistry panels, urinalyses, radiographs, joint fluid analyses, MRI/positron emission tomography scans, scintigraphy, and biodistribution scans. On day 45-47, each dog was euthanized and a complete postmortem examination was performed. Tissue samples were submitted for histopathology and radioisotope retention studies. Left elbow joints were decalcified and sectioned for future autoradiography. Scintigraphy, 1 day after injection, indicated slight radioisotope escape from the joint to regional lymph nodes. Serial blood, urine, feces, and organ counts indicated >99.1% of the 117m Sn activity was retained in the joint for 45-47 days. Radiation output levels were below patient release levels the day following injection. Maximum standard uptake value for the injected joint decreased. Joint fluid cytology was unchanged. No dog exhibited lameness during the study. Absence of joint damage and lack of systemic effects after injection of the 117m Sn colloid in normal canine elbow joints indicate that this agent may be safely used for radiosynoviorthesis in dogs with osteoarthritis.

Poster: EANM 19 / EPS-128 / A Novel Sn-117m Colloid for Human Radiosynoviorthesis Clinical Trials by: N. R. Stevenson1, C. A. Doerr1, G. R. Gonzales1, J. Simon2, A. Bendele3; 1Serene, LLC, Buford, UNITED STATES OF AMERICA, 2IsoTherapeutics Group, LLC, Angleton, UNITED STATES OF AMERICA, 3Bolder BioPATH, Inc., Boulder, UNITED STATES OF AMERICA

Introduction: Radiosynoviorthesis (a.k.a. radiosynovectomy) treats arthritis by the intraarticular injection of a radioactive colloid. The radionuclides that are most often used are Y90 for large joints, Re-186 for medium-sized joints and Er-169 for small joints, along with P32 for treating hemophilic arthropathy. An ongoing trial of a novel colloid of Sn-117m, which emits therapeutic conversion electrons (~140 keV, 112%; range ~300 um), is producing very encouraging results in the treatment of arthritic canine elbow joints. These are comparable in size to some human joints. The 14-day physical half-life of Sn-117m allows time for phagocytosis and migration of the radioactive particles deeper into the tissue. It is thus conceivable that Sn-117m could treat larger joints with thicker synovia while still sparing the cartilage and bone. This study simulated moving distributions of the radionuclides in order to estimate the radiation absorbed dose in the structures of a treated joint.

Objectives: A Tc-99m labeled mannosyl-dextran molecule (Tc-99m tilmanocept) has demonstrated specificity for targeting CD206 macrophages associated with sentinel nodes in breast cancer patients. The CD206 receptor is also expressed on inflammatory cells in the joints of patients with rheumatoid arthritis (RA) and in other inflammatory conditions (such as atherosclerosis) [1]. In patients with advanced RA, direct injections of radiocolloid into affected joints are used therapeutically to relieve pain and increase mobility. RA rarely effects a single joint, so multiple injections at multiple sites are required. If the radiocolloid could be administered systemically, it may be possible to treat multiple joints simultaneously. We combined a therapeutic isotope, Sn117m (γ 159 keV, 86% ; e ~140 keV, 112% ; t1⁄2 14d) with mannosyl-dextran to test the ability of the therapeutic tracer to localize in sites of inflammation in similar fashion to Tc-99m tilmanocept.

474 Objectives: Tin-117m is a promising radionuclide for the treatment of arthritis. Currently, radiosynoviorthesis employs Y-90 or P-32 for large joints, Re-186 for medium-sized joints and Er-169 for small joints based upon the energies and hence the ranges of their emitted beta particles. This study sought to demonstrate the utility of a Sn-117m colloid in the treatment of various sized joints. While the 300 µm range of its conversion electrons makes it intrinsically suitable for small joints, its relatively long 14-day half-life might allow the colloidal particles to be transported by macrophages deeper into the synovial tissues and thereby effectively treat larger joints. Methods: Static and dynamic models of Sn-117m radiosynoviorthesis were developed using the Geant4 Application for Emission Tomography (GATE) Monte-Carlo software. The geometry of a synovial joint in the simulation was adopted from the planar layered model in the dissertation of LS Johnson. All five radionuclides were simulated in both static and dynamic situations. The 6 µm colloidal particles labeled with one of the radionuclides were initially arrayed in a rectilinear grid with a center-to-center spacing of 0.1 mm in a plane at the interface between the joint capsule and the intima. In the dynamic model, the particles then moved perpendicular to the planes of the joint layers with a uniform distribution of velocities. Their maximum speed of 8.58×10-8 mm/s was estimated from an analysis of post-mortem autoradiographs of the elbows of treated dogs. The dose as a function of depth in the model was plotted for both the static and dynamic models for all five radionuclides. Results: The activity that was required to deliver the same peak dose as that from 1 MBq/cm2 of Sn-117m was 7.68 MBq/cm2 of Y-90, 2.07 MBq/cm2 of Er-169, 4.74 MBq/cm2 of Re-186, and 1.41 MBq/cm2 of P-32 in the static simulation and 5.30 MBq/cm2 of Y-90, 1.81 MBq/cm2 of Er-169, 3.38 MBq/cm2 of Re-186, and 1.16 MBq/cm2 of P-32 in the dynamic simulation. The shapes of the dose distribution curves were very similar for Sn-117m and Er-169. Tin-117m and Re-186 can each deliver 100 Gy as deeply as 0.5 mm into the synovial tissue with dosages of 4.19 MBq/cm2 and 1.46 MBq/cm2 respectively. Conclusions: Tin-117m could be substituted for Re-186 in the treatment of medium-sized joints as well as for Er-169 in the treatment of small joints. Research Support: This work was supported by an unrestricted grant from Serene, LLC and by the Center for the Integration of STEM Education & Research (CISER) Undergraduate Research Program at Texas Tech University.

477 Objectives: Radiosynoviorthesis using a tin-117m colloid is proving to be an effective treatment of osteoarthritis of the canine elbow. This study used new clinical measurements of external exposure and Monte Carlo simulations in order to develop guidelines for the release of treated animals from radiation safety isolation based upon the public dose limit of 1 mSv. Methods: Twelve adult dogs were treated with the Sn-117m colloid for Grade 3 osteoarthritis of the elbow. The nominal dosage of 1.75 mCi to an elbow of a 50 pound dog was adjusted by weight-based body surface area and capped at 3 mCi. Nine dogs were treated in both elbows and three were treated in just one. They weighed 73.8±16.4 [50-101] pounds and received 3.7±1.3 [1.6-5.6] mCi in all. The external exposure rate was measured using a Ludlum 9DP ionization meter laterally at distances of 5 cm and 1 m and cranially at a distance of 1 m as soon as the dogs awoke from sedation and again on the next day. These situations were simulated in a stylized fashion using the Gate Monte Carlo software. For release calculations, walking and playing with a dog were modeled as separation by 3 feet while feeding and petting a dog were modeled as separation by 1 foot. Results: The simulation of a point source in air gave a dose rate constant of 1.54×10-17 Gy-m2/Bq-s at a depth of 1 cm into water, which is mid-way between the extreme values calculated using the ANSI/ANS-6.1.1-1991 methodology. The simulation of two legs gave an attenuation of the dose from the far joint of 50%. Including this effect, the measured lateral dose rate at 1 m was 52% of the expected dose rate in air and the cranial dose rate was 37% of that expected in air, so for release calculations, an effective dose rate of 8.0×10-18 Gy-m2/Bq-s was used regardless of orientation. The measurements that were made immediately post-treatment and those from the next day did not differ significantly. The restrictions on an individual person’s interacting with dogs that were given the maximum dosage of this cohort or the nominal dosage for modeled exposure times while keeping the person’s total dose below 1 mSv are tabulated. After ten weeks (or five physical half-lives), more relaxed restrictions would typically allow a further dose of only 0.15 mSv or less. Conclusions: Dogs that have been treated with Sn-117m radiosynoviorthesis may be released from radiation safety isolation immediately after treatment with tolerable restrictions on human interactions.

The following definitions are presented in the order that they appear in this report. Synovial inflammation is strongly implicated in the pathogenesis of osteoarthritis (OA) and other arthropathies. Synovitis is a common feature of symptomatic but pre-radiographic OA. This indicates that chronic, early-stage joint inflammation occurs well before significant radiographic changes and drives progression toward cartilage loss, osteophyte formation, bone remodeling, and joint space narrowing.1-3 The pathology of early-onset synovitis and its role in OA has been well characterized. Whereas normal synovium is two or three cell layers thick and devoid of inflammatory cells, synovitis results in a number of profound changes in synovial tissue and the joint micro-environment. These include marked hyperplasia and permeability of the synovial lining, significant over-expression of pro-inflammatory mediators and cytokines, infiltration of inflammatory cells, production of degradative enzymes, synovial neo-vascularization, and increased serum C-reactive protein, a biomarker of inflammation.1,2,4-6 The inflammatory response sensitizes peripheral neurons in synovial tissue, resulting in a pain response.7

323 Objectives To demonstrate the therapeutic effects of a novel homogeneous Sn-117m colloid (HTC) delivered intra-articularly in a GLP rat osteoarthritis (OA) model in order to validate the effects seen in prior non-GLP rat OA trials. Radiosynoviorthesis utilizing Sn-117m as demonstrated in this rat OA model may be considered for the treatment of OA in other species. Methods Sn-117m (t½ 14 days) decays by isomeric transition, producing both gamma rays at 159 keV, (86% abundant), and monoenergetic conversion electrons (~140 keV; >110%) with a range of ~300 µm in tissue. We administered our previously described HTC with colloid particles averaging 5.33um, and 80% between 3.05µm and 9.63µm. The HTC was tested in a surgically induced OA rat model (n=90). All rats were treated with a single intra-articular injection of 2µCi or 10µCi in the left knee. Two control groups also were included. Data collection and analysis completed at various time-points included blood work, urine and fecal radiation excretion, histopathology, and bio-distribution. Rats were sacrificed at 7 days, 28 days (2 t½), 42 days (3 t½), and 70 days (5 t½) after injection. Results All animals behaved normally following surgery and HTC injection. Joint retention of the HTC, when correctly administered, was >99.0%. Blood work remained unremarkable throughout the study. Urinary and fecal cumulative radiation excretion averaged Conclusions These results validate and build upon those of prior non-GLP studies, and lead us to conclude: (1) HTC is significantly retained in the joint space when properly administered thus mitigating the likelihood of unintended distal tissue irradiation, (2) following administration, there are no clinical safety concerns as noted by normal rat behavior, (3) fecal and urinary radiation excretion is nominal immediately following HTC administration, suggesting the ability to rapidly release rats from radiation isolation, (4) histopathology indicates a positive therapeutic effect of two doses in this rat model. As a result of these positive data, we have begun a pivotal trial to treat naturally occurring elbow osteoarthritis in dogs with a weight-appropriate dose of HTC.