Preparation and PET/CT imaging of implant directed 68Ga-labeled magnetic nanoporous silica nanoparticles.

BACKGROUND: Implant infections caused by biofilm forming bacteria are a major threat in orthopedic surgery. Delivering antibiotics directly to an implant affected by a bacterial biofilm via superparamagnetic nanoporous silica nanoparticles could present a promising approach. Nevertheless, short blood circulation half-life because of rapid interactions of nanoparticles with the host's immune system hinder them from being clinically used. The aim of this study was to determine the temporal in vivo resolution of magnetic nanoporous silica nanoparticle (MNPSNP) distribution and the effect of PEGylation and clodronate application using PET/CT imaging and gamma counting in an implant mouse model. METHODS: PEGylated and non-PEGylated MNPSNPs were radiolabeled with gallium-68 (68Ga), implementing the chelator tris(hydroxypyridinone). 36 mice were included in the study, 24 mice received a magnetic implant subcutaneously on the left and a titanium implant on the right hind leg. MNPSNP pharmacokinetics and implant accumulation was analyzed in dependence on PEGylation and additional clodronate application. Subsequently gamma counting was performed for further final analysis. RESULTS: The pharmacokinetics and biodistribution of all radiolabeled nanoparticles could clearly be visualized and followed by dynamic PET/CT imaging. Both variants of 68Ga-labeled MNPSNP accumulated mainly in liver and spleen. PEGylation of the nanoparticles already resulted in lower liver uptakes. Combination with macrophage depletion led to a highly significant effect whereas macrophage depletion alone could not reveal significant differences. Although MNPSNP accumulation around implants was low in comparison to the inner organs in PET/CT imaging, gamma counting displayed a significantly higher %I.D./g for the tissue surrounding the magnetic implants compared to the titanium control. Additional PEGylation and/or macrophage depletion revealed no significant differences regarding nanoparticle accumulation at the implantation site. CONCLUSION: Tracking of 68Ga-labeled nanoparticles in a mouse model in the first critical hours post-injection by PET/CT imaging provided a better understanding of MNPSNP distribution, elimination and accumulation. Although PEGylation increases circulation time, nanoparticle accumulation at the implantation site was still insufficient for infection treatment and additional efforts are needed to increase local accumulation.

Molecular imaging of the brain-heart axis provides insights into cardiac dysfunction after cerebral ischemia.

Ischemic stroke imparts elevated risk of heart failure though the underlying mechanisms remain poorly described. We aimed to characterize the influence of cerebral ischemic injury on cardiac function using multimodality molecular imaging to investigate brain and cardiac morphology and tissue inflammation in two mouse models of variable stroke severity. Transient middle cerebral artery occlusion (MCAo) generated extensive stroke damage (56.31 ± 40.39 mm3). Positron emission tomography imaging of inflammation targeting the mitochondrial translocator protein (TSPO) revealed localized neuroinflammation at 7 days after stroke compared to sham (3.8 ± 0.8 vs 2.6 ± 0.7 %ID/g max, p < 0.001). By contrast, parenchyma topical application of vasoconstrictor endothelin-1 did not generate significant stroke damage or neuroinflammatory cell activity. MCAo evoked a modest reduction in left ventricle ejection fraction at both 1 weeks and 3 weeks after stroke (LVEF at 3 weeks: 54.3 ± 5.7 vs 66.1 ± 3.5%, p < 0.001). This contractile impairment was paralleled by elevated cardiac TSPO PET signal compared to sham (8.6 ± 2.4 vs 5.8 ± 0.7%ID/g, p = 0.022), but was independent of leukocyte infiltration defined by flow cytometry. Stroke size correlated with severity of cardiac dysfunction (r = 0.590, p = 0.008). Statistical parametric mapping identified a direct association between neuroinflammation at 7 days in a cluster of voxels including the insular cortex and reduced ejection fraction (ρ = - 0.396, p = 0.027). Suppression of microglia led to lower TSPO signal at 7 days which correlated with spared late cardiac function after MCAo (r = - 0.759, p = 0.029). Regional neuroinflammation early after cerebral ischemia influences subsequent cardiac dysfunction. Total body TSPO PET enables monitoring of neuroinflammation, providing insights into brain-heart inter-organ communication and may guide therapeutic intervention to spare cardiac function post-stroke.

Dissecting the target leukocyte subpopulations of clinically relevant inflammation radiopharmaceuticals.

BACKGROUND: Leukocyte subtypes bear distinct pro-inflammatory, reparative, and regulatory functions. Imaging inflammation provides information on disease prognosis and may guide therapy, but the cellular basis of the signal remains equivocal. We evaluated leukocyte subtype specificity of characterized clinically relevant inflammation-targeted radiotracers. METHODS AND RESULTS: Leukocyte populations were purified from blood- and THP-1-derived macrophages were polarized into M1-, reparative M2a-, or M2c-macrophages. In vitro uptake assays were conducted using tracers of enhanced glucose or amino acid metabolism and molecular markers of inflammatory cells. Both 18F-deoxyglucose (18F-FDG) and the labeled amino acid 11C-methionine (11C-MET) displayed higher uptake in neutrophils and monocytes compared to other leukocytes (P = 0.005), and markedly higher accumulation in pro-inflammatory M1-macrophages compared to reparative M2a-macrophages (P < 0.001). Molecular tracers 68Ga-DOTATATE targeting the somatostatin receptor type 2 and 68Ga-pentixafor targeting the chemokine receptor type 4 (CXCR4) exhibited broad uptake by leukocyte subpopulations and polarized macrophages with highest uptake in T-cells/natural killer cells and B-cells compared to neutrophils. Mitochondrial translocator protein (TSPO)-targeted 18F-flutriciclamide selectively accumulated in monocytes and pro-inflammatory M1 macrophages (P < 0.001). Uptake by myocytes and fibroblasts tended to be higher for metabolic radiotracers. CONCLUSIONS: The different in vitro cellular uptake profiles may allow isolation of distinct phases of the inflammatory pathway with specific inflammation-targeted radiotracers. The pathogenetic cell population in specific inflammatory diseases should be considered in the selection of an appropriate imaging agent.

Proof-of-concept that network pharmacology is effective to modify development of acquired temporal lobe epilepsy.

Epilepsy is a complex network phenomenon that, as yet, cannot be prevented or cured. We recently proposed network-based approaches to prevent epileptogenesis. For proof of concept we combined two drugs (levetiracetam and topiramate) for which in silico analysis of drug-protein interaction networks indicated a synergistic effect on a large functional network of epilepsy-relevant proteins. Using the intrahippocampal kainate mouse model of temporal lobe epilepsy, the drug combination was administered during the latent period before onset of spontaneous recurrent seizures (SRS). When SRS were periodically recorded by video-EEG monitoring after termination of treatment, a significant decrease in incidence and frequency of SRS was determined, indicating antiepileptogenic efficacy. Such efficacy was not observed following single drug treatment. Furthermore, a combination of levetiracetam and phenobarbital, for which in silico analysis of drug-protein interaction networks did not indicate any significant drug-drug interaction, was not effective to modify development of epilepsy. Surprisingly, the promising antiepileptogenic effect of the levetiracetam/topiramate combination was obtained in the absence of any significant neuroprotective or anti-inflammatory effects as indicated by multimodal brain imaging and histopathology. High throughput RNA-sequencing (RNA-seq) of the ipsilateral hippocampus of mice treated with the levetiracetam/topiramate combination showed that several genes that have been linked previously to epileptogenesis, were significantly differentially expressed, providing interesting entry points for future mechanistic studies. Overall, we have discovered a novel combination treatment with promise for prevention of epilepsy.

Reliable quantification of 18F-GE-180 PET neuroinflammation studies using an individually scaled population-based input function or late tissue-to-blood ratio.

PURPOSE: Tracer kinetic modeling of tissue time activity curves and the individual input function based on arterial blood sampling and metabolite correction is the gold standard for quantitative characterization of microglia activation by PET with the translocator protein (TSPO) ligand 18F-GE-180. This study tested simplified methods for quantification of 18F-GE-180 PET. METHODS: Dynamic 18F-GE-180 PET with arterial blood sampling and metabolite correction was performed in five healthy volunteers and 20 liver-transplanted patients. Population-based input function templates were generated by averaging individual input functions normalized to the total area under the input function using a leave-one-out approach. Individual population-based input functions were obtained by scaling the input function template with the individual parent activity concentration of 18F-GE-180 in arterial plasma in a blood sample drawn at 27.5 min or by the individual administered tracer activity, respectively. The total 18F-GE-180 distribution volume (VT) was estimated in 12 regions-of-interest (ROIs) by the invasive Logan plot using the measured or the population-based input functions. Late ROI-to-whole-blood and ROI-to-cerebellum ratio were also computed. RESULTS: Correlation with the reference VT (with individually measured input function) was very high for VT with the population-based input function scaled with the blood sample and for the ROI-to-whole-blood ratio (Pearson correlation coefficient = 0.989 ± 0.006 and 0.970 ± 0.005). The correlation was only moderate for VT with the population-based input function scaled with tracer activity dose and for the ROI-to-cerebellum ratio (0.653 ± 0.074 and 0.384 ± 0.177). Reference VT, population-based VT with scaling by the blood sample, and ROI-to-whole-blood ratio were sensitive to the TSPO gene polymorphism. Population-based VT with scaling to the administered tracer activity and the ROI-to-cerebellum ratio failed to detect a polymorphism effect. CONCLUSION: These results support the use of a population-based input function scaled with a single blood sample or the ROI-to-whole-blood ratio at a late time point for simplified quantitative analysis of 18F-GE-180 PET.

Ex vivo characterization of neuroinflammatory and neuroreceptor changes during epileptogenesis using candidate positron emission tomography biomarkers.

OBJECTIVE: Identification of patients at risk of developing epilepsy before the first spontaneous seizure may promote the development of preventive treatment providing opportunity to stop or slow down the disease. METHODS: As development of novel radiotracers and on-site setup of existing radiotracers is highly time-consuming and expensive, we used dual-centre in vitro autoradiography as an approach to characterize the potential of innovative radiotracers in the context of epilepsy development. Using brain slices from the same group of rats, we aimed to characterise the evolution of neuroinflammation and expression of inhibitory and excitatory neuroreceptors during epileptogenesis using translational positron emission tomography (PET) tracers; 18 F-flumazenil (18 F-FMZ; GABAA receptor), 18 F-FPEB (metabotropic glutamate receptor 5; mGluR5), 18 F-flutriciclamide (translocator protein; TSPO, microglia activation) and 18 F-deprenyl (monoamine oxidase B, astroglia activation). Autoradiography images from selected time points after pilocarpine-induced status epilepticus (SE; baseline, 24 and 48 hours, 5, 10 and 15 days and 6 and 12-14 weeks after SE) were normalized to a calibration curve, co-registered to an MRI-based 2D region-of-interest atlas, and activity concentration (Bq/mm2 ) was calculated. RESULTS: In epileptogenesis-associated brain regions, 18 F-FMZ and 18 F-FPEB showed an early decrease after SE. 18 F-FMZ decrease was maintained in the latent phase and further reduced in the chronic epileptic animals, while 18 F-FPEB signal recovered from day 10, reaching baseline levels in chronic epilepsy. 18 F-flutriciclamide showed an increase of activated microglia at 24 hours after SE, peaking at 5-15 days and decreasing during the chronic phase. On the other hand, 18 F-deprenyl autoradiography showed late astrogliosis, peaking in the chronic phase. SIGNIFICANCE: Autoradiography revealed different evolution of the selected targets during epileptogenesis. Our results suggest an advantage of combined imaging of inter-related targets like glutamate and GABAA receptors, or microglia and astrocyte activation, in order to identify important interactions, especially when using PET imaging for the evaluation of novel treatments.

177Lu Labeled Cyclic Minigastrin Analogues with Therapeutic Activity in CCK2R Expressing Tumors: Preclinical Evaluation of a Kit Formulation.

Minigastrin (MG) analogues specifically target cholecystokinin-2 receptors (CCK2R) expressed in different tumors and enable targeted radiotherapy of advanced and disseminated disease when radiolabeled with a beta emitter such as 177Lu. Especially truncated MG analogues missing the penta-Glu sequence are associated with low kidney retention and seem therefore most promising for therapeutic use. Based on [d-Glu1,desGlu2-6]MG (MG11) we have designed the two cyclic MG analogues cyclo1,9[γ-d-Glu1,desGlu2-6,d-Lys9]MG (cyclo-MG1) and cyclo1,9[γ-d-Glu1,desGlu2-6,d-Lys9,Nle11]MG (cyclo-MG2). In the present work we have developed and preclinically evaluated a pharmaceutical kit formulation for the labeling with 177Lu of the two DOTA-conjugated cyclic MG analogues. The stability of the kits during storage as well as the stability of the radiolabeled peptides was investigated. A cell line stably transfected with human CCK2R and a control cell line without receptor expression were used for in vitro and in vivo studies with the radioligands prepared from kit formulations. In terms of stability 177Lu-DOTA-cyclo-MG2 showed advantages over 177Lu-DOTA-cyclo-MG1. Still, for both radioligands a high receptor-mediated cell uptake and favorable pharmacokinetic profile combining receptor-specific tumor uptake with low unspecific tissue uptake and low kidney retention were confirmed. Investigating the therapy efficacy and treatment toxicity in xenografted BALB/c nude mice a receptor-specific and comparable therapeutic effect could be demonstrated for both radioligands. A 1.7- to 2.6-fold increase in tumor volume doubling time was observed for receptor-positive tumors in treated versus untreated animals, which was 39-73% higher when compared to receptor-negative tumors. The treatment was connected with transient bone marrow toxicity and minor signs of kidney toxicity. All together the obtained results support further studies for the clinical translation of this new therapeutic approach.

Synthesis of GPR40 targeting 3 H- and 18 F-probes towards selective beta cell imaging.

Diabetes affects an increasing number of patients worldwide and is responsible for a significant rise in healthcare expenses. Imaging of ß-cells in vivo is expected to contribute to an improved understanding of the underlying pathophysiology, improved diagnosis, and development of new treatment options for diabetes. Here, we describe the first radiosyntheses of [3 H]-TAK875 and [18 F]-TAK875 derivatives to be used as ß-cell imaging probes addressing the free fatty acid receptor 1 (FFAR1/GPR40). The fluorine-labeled derivative showed similar agonistic activity as TAK875 in a functional assay. The radiosynthesis of the 18 F-labelled tracer 2a was achieved with 16.7 ± 5.7% radiochemical yield in a total synthesis time of 60-70 min.

[SPECT radiopharmaceuticals -- novelties and new possibilities]. / SPECT-radiofarmakonok -- újdonságok és új lehetoségek.

Actual state of affairs and future perspectives of SPECT radiopharmaceuticals regarding local and international data were summarized. Beyond conventional gamma-emitting radioisotopes, localization studies with beta emitting therapeutic radiopharmaceuticals hold increasing importance. Extension of hybrid (SPECT/CT) equipments has modified conventional scintigraphic and SPECT methods as well but more important changes come into the world through novel ligands for specific diagnoses and therapy.

Implant Imaging: Perspectives of Nuclear Imaging in Implant, Biomaterial, and Stem Cell Research.

Until now, very few efforts have been made to specifically trace, monitor, and visualize implantations, artificial organs, and bioengineered scaffolds for tissue engineering in vivo. While mainly X-Ray, CT, and MRI methods have been used for this purpose, the applications of more sensitive, quantitative, specific, radiotracer-based nuclear imaging techniques remain a challenge. As the need for biomaterials increases, so does the need for research tools to evaluate host responses. PET (positron emission tomography) and SPECT (single photon emission computer tomography) techniques are promising tools for the clinical translation of such regenerative medicine and tissue engineering efforts. These tracer-based methods offer unique and inevitable support, providing specific, quantitative, visual, non-invasive feedback on implanted biomaterials, devices, or transplanted cells. PET and SPECT can improve and accelerate these studies through biocompatibility, inertivity, and immune-response evaluations over long investigational periods at high sensitivities with low limits of detection. The wide range of radiopharmaceuticals, the newly developed specific bacteria, and the inflammation of specific or fibrosis-specific tracers as well as labeled individual nanomaterials can represent new, valuable tools for implant research. This review aims to summarize the opportunities of nuclear-imaging-supported implant research, including bone, fibrosis, bacteria, nanoparticle, and cell imaging, as well as the latest cutting-edge pretargeting methods.

Simplified 89Zr-Labeling Protocol of Oxine (8-Hydroxyquinoline) Enabling Prolonged Tracking of Liposome-Based Nanomedicines and Cells.

In this work, a method for the preparation of the highly lipophilic labeling synthon [89Zr]Zr(oxinate)4 was optimized for the radiolabeling of liposomes and human induced pluripotent stem cells (hiPSCs). The aim was to establish a robust and reliable labeling protocol for enabling up to one week positron emission tomography (PET) tracing of lipid-based nanomedicines and transplanted or injected cells, respectively. [89Zr]Zr(oxinate)4 was prepared from oxine (8-hydroxyquinoline) and [89Zr]Zr(OH)2(C2O4). Earlier introduced liquid-liquid extraction methods were simplified by the optimization of buffering, pH, temperature and reaction times. For quality control, thin-layer chromatography (TLC), size-exclusion chromatography (SEC) and centrifugation were employed. Subsequently, the 89Zr-complex was incorporated into liposome formulations. PET/CT imaging of 89Zr-labeled liposomes was performed in healthy mice. Cell labeling was accomplished in PBS using suspensions of 3 × 106 hiPSCs, each. [89Zr]Zr(oxinate)4 was synthesized in very high radiochemical yields of 98.7% (96.8% ± 2.8%). Similarly, high internalization rates (≥90%) of [89Zr]Zr(oxinate)4 into liposomes were obtained over an 18 h incubation period. MicroPET and biodistribution studies confirmed the labeled nanocarriers' in vivo stability. Human iPSCs incorporated the labeling agent within 30 min with ~50% efficiency. Prolonged PET imaging is an ideal tool in the development of lipid-based nanocarriers for drug delivery and cell therapies. To this end, a reliable and reproducible 89Zr radiolabeling method was developed and tested successfully in a model liposome system and in hiPSCs alike.

Impact of DOTA-Chelators on the Antitumor Activity of 177Lu-DOTA-Rituximab Preparations in Lymphoma Tumor-Bearing Mice.

Background: This work aimed to evaluate the influence of two chelators: DOTA(SCN) and DOTA(NHS) on radioimmunotherapy using 177Lu-DOTA-Rituximab preparations in murine lymphoma xenograft models. Subsequently, based on animal data, the organ radiation-absorbed doses were extrapolated to humans (adult male). Materials and Methods: Therapeutic efficacy of 177Lu-DOTA-Rituximab was evaluated in male nude mice bearing either Raji (B lymphocyte, CD20+) and Jurkat (T lymphocyte, CD20) xenografts, utilizing an anti-CD20 antibody-Rituximab conjugate with either DOTA(SCN) or DOTA(NHS). The DOTA-Rituximab conjugates were prepared in the form of freeze-dried kits. Results: All radioimmunoconjugates were obtained with high radiolabeling yield (radiochemical purity, RCP > 95%) and specific activity of ca. 0.5 GBq/mg. Therapeutic effects of 177Lu-DOTA-Rituximab were observed in animals regardless whether DOTA(SCN) or DOTA(NHS) were used for conjugation. Importantly, therapy involving 177Lu-DOTA-Rituximab was more effective than use of Rituximab alone. Conclusions: The degree of antitumor efficacy was dependent on the type of applied bifunctional chelators conjugated to mAb. However, this difference was not statistically significant. Dosimetry calculations showed that the absorbed radiation doses extrapolated to humans were very low for osteogenic cells regardless of the conjugates. Organs like the liver and spleen, treated with 177Lu-DOTA(SCN)-Rituximab, showed similar radiation absorbed doses when compared with 177Lu-DOTA(NHS)-Rituximab.

Nanoparticles for SPECT and PET Imaging: Towards Personalized Medicine and Theranostics.

BACKGROUND: PET and SPECT imaging methods can be of excellent assistance for the development of new nanoparticle drug delivery systems, and at the same time, these investigations also offer the opportunity to produce exceptional new diagnostic and therapeutic radiopharmaceuticals, as well. With a multifunctional, nano-scaled drug delivery system, the diagnostic (imaging) methods and the therapy (delivering drugs or beta-emitter radionuclides) can be carried out using the same biological and pharmacological mechanisms. By combining therapy and diagnostics in one method or in one specifically targeted nanoparticle system, we can product theranostic pharmaceuticals, and its applications are important elements of personalized medicine. OBJECTIVES: This review takes a short historical look back to the radiocolloids, the great ancestors of (radiolabeled) nanoparticles and then describes the general features of current types of PET and SPECT imaging associated nanoparticle-based products and key radiolabeling methods; entering into details of potential prospective challenges related to radiotheranostic approaches and imaging guided therapy.

Preparation and 68Ga-radiolabeling of porous zirconia nanoparticle platform for PET/CT-imaging guided drug delivery.

This paper describes the preparation of gallium-68 (68Ga) isotope labeled porous zirconia (ZrO2) nanoparticle (NP) platform of nearly 100nm diameter and its first pharmacokinetic and biodistribution evaluation accomplished with a microPET/CT (µPet/CT) imaging system. Objectives of the investigations were to provide a nanoparticle platform which can be suitable for specific delivery of various therapeutic drugs using surface attached specific molecules as triggering agents, and at the same time, suitable for positron emission tomography (PET) tracing of the prospective drug delivery process. Radiolabeling was accomplished using DOTA bifunctional chelator. DOTA was successfully adsorbed onto the surface of nanoparticles, while the 68Ga-radiolabeling method proved to be simple and effective. In the course of biodistribution studies, the 68Ga-labeled DOTA-ZrNPs showed proper radiolabeling stability in their original suspension and in blood serum. µPet/CT imaging studies confirmed a RES-biodistribution profile indicating stable nano-sized labeled particles in vivo. Results proved that the new method offers the opportunity to examine further specifically targeted and drug payload carrier variants of zirconia NP systems using PET/CT imaging.

Temperature increase induced by modulated electrohyperthermia (oncothermia®) in the anesthetized pig liver.

AIM OF STUDY: Is to show the intrahepatic temperature development in anesthetized pig. MATERIALS AND METHODS: Temperature development in the liver of anesthetized pig is measured to study the thermal effects of capacitive coupled energy transfer. The treatment was made by modulated electrohyperthermia (mEHT, trade name: oncothermia ®), controlled by a fluoroptical temperature sensing positioned by the ultrasound-guided process. Various fits of coupling were studied. RESULTS: The intrahepatic temperature at the end of the treatment ranged 40.5-44.8°C, while the skin temperature ranged 36.8-41.8°C depending on the coupling arrangement. CONCLUSION: mEHT is a feasible method to deliver deep heat to the liver of an anesthetized pig.

Evaluation of ¹77Lu-EDTMP in Dogs with Spontaneous Tumor Involving Bone: Pharmacokinetics, Dosimetry and Therapeutic Efficacy.

177Lu-EDTMP is currently being investigated as a potential agent for providing palliative care to the patients suffering from bone pain due to metastatic skeletal carcinoma. The present article describes the evaluation of 177Lu-EDTMP complex in four different canine patients with different types of primary and metastatic skeletal lesions with respect to its pharmacokinetic properties, dosimetry and therapeutic efficacy. The dogs were treated with a dose of ~44.4 MBq (1.2 mCi) per kg body weight of 177Lu-EDTMP, synthesized in-house with high radiochemical purity (98.8 ± 0.4 %) and excellent in vitro stability. The radiopharmaceutical showed favourable pharmacokinetic properties, such as, preferential accumulation at skeletal lesion sites and fast clearance from blood and other non-target organs through urinary route. The administered dose of the radiopharmacutical showed excellent therapeutic efficacy in case of a dog suffering from skeletal metastasis originating from primary tumor elsewhere. On the other hand, two of the remaining three patients with primary bone cancer showed stable disease intially with palliative effect. The fourth patient having metal implant induced osteosarcoma with severe limb oedema did not show any response to the treatment.

Lu-177-Labeled Zirconia Particles for Radiation Synovectomy.

The present article describes the preparation of ß-emitter lutetium-177-labeled zirconia colloid and its preliminary physicochemical and biological evaluation of suitability for local radionuclide therapy. The new (177)Lu-labeled therapeutic radiopharmaceutical candidate was based on the synthesis mode of a previously described zirconia nanoparticle system. The size and shape of the developed radiopharmaceutical compound were observed through a scanning electron microscope and dynamic light scattering methods. The radiocolloid had a 1.7 µm mean diameter and showed high in vitro radiochemical and colloid size stability at room temperature and during the blood sera stability test. After the in vitro characterizations, the product was investigated in the course of the treatment of a spontaneously diseased dog veterinary patient's hock joint completed with single-photon emission computed tomography (SPECT) imaging follow-up measurements and a dual-isotope SPECT imaging tests with conventional (99m)Tc-methanediphosphonic acid bone scintigraphy. In the treated dog, no clinical side-effects or signs of histopathological changes of the joints were recorded during the treatment. SPECT follow-up studies clearly and conspicuously showed the localization of the (177)Lu-labeled colloid in the hock joint as well as detectable but negligible leakages of the radiocolloid in the nearest lymph node. On the basis of biological follow-up tests, the orthopedic team assumed that the (177)Lu-labeled zirconia colloid-based local radionuclide therapy resulted in a significant and long-term improvement in clinical signs of the patient without any remarkable side-effects.

Distribution of N-methyl-(14)C-labeled selegiline in the rat.

Tissue distribution of selegiline including N-methyl-(14)C-selegiline was studied with three different techniques. Whole body autoradiography of labeled selegiline in rats completed the former results obtained in mice. Counting radioactivity by liquid scintillation method in various body compartments gave an in-depth numerical estimation of distribution, while RP-HPLC determination of selegiline determined the fate of intact, non-metabolized parent compound. Whole body autoradiography following 15 and 60 min of intraperitoneal application of N-methyl-(14)C-selegiline verified definite and time-dependent blood-brain penetration of selegiline. Quantitative determination of tissue concentrations by liquid scintillation and RP-HPLC methods following 5, 15, 60 and 180 min of intraperitoneal administration of selegiline unanimously verified both blood-brain and blood-testis penetration of the compound through the barrier.

Preliminary studies with 188rhenium-tin colloid for radiation synovectomy: preparation, size determination, in-vivo distribution, effect and dosimetry studies.

BACKGROUND: Generator-produced beta-emitting radionuclides such as (188)Re are gaining in importance for radiosynoviorthesis because of their availability on a regular basis. MATERIAL AND METHODS: We prepared a (188)Re-tin colloid in a reaction carried out either at 100 degrees C or at room temperature (RT). The size of the colloid particles was measured with a laser lightscattering method, and their biodistribution, dosimetric aspects and therapeutic effects were studied in an antigen-induced arthritis (AIA) model in rabbits. (188)Re-tin colloid solution was injected intra-articularly into the knee joints of rabbits with AIA and imaging studies were performed. Blood samples were collected post injection for estimation of the blood residence time. We also injected 2 intact rabbits in the same manner with (188)Re perrhenate solution in order to observe its effects and distribution in the body. All the treated rabbit knees were subjected to histopathology. RESULTS: The colloid particle size distribution was different after preparation at the different reaction temperatures, with a more suitable mean of 4.53 micro m in the RT preparation. The dose delivered to the synovial surface was between 3.51 and 4.21 Gy and that to the bone surface was between 0.70 and 0.84 Gy. Histopathologic examination revealed the development of fibrous connective tissue in the AIA knees 4 weeks after treatment, but not in the control group. CONCLUSIONS: The (188)Re-tin colloid preparation used in this study was suitable for radiation synovectomy application. It requires modifications in the preparation protocol so as to increase the labeling efficiency in correlation with an appropriate particle size.

Sentinel lymph node detection in canine oncological patients.

BACKGROUND: Sentinel lymph node detection was investigated in dogs with spontaneously occurring tumours. MATERIAL AND METHODS: In this pilot study, 24 client-owned spontaneously tumorous dogs presented for sentinel lymph node detection. A multiple method was used with a nuclear medicine technique (injection of 99mTc human serum albumin colloid) with scintigraphy and intraoperative guidance, and blue dye injection. RESULTS: Of the 35 lymph nodes histologically demonstrated to contain metastases, 34 (97%) were found by radioguided surgery, which means that one would have been missed in the intraoperative localisation process; 31 nodes (89%) were clearly visualised in the gamma camera images; only 27 (77%) were blue-stained by vital dye; a mere 8 lymph nodes (23%) were enlarged and therefore easily detectable by palpation. CONCLUSIONS: Data obtained from the harmless application of the sentinel node concept are useful for the radiopharmaceutist. The sentinel lymph node concept is well applicable in the veterinary clinic.