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It has in recent years been reported that microemulsion (ME) delivery systems provide an opportunity to improve the efficacy of a therapeutic agent whilst minimising side effects and also offer the advantage of favourable treatment regimens. The prostate‐specific membrane antigen (PSMA) targeting agents PSMA‐11 and PSMA‐617, which accumulate in prostate tumours, allow for [68Ga]Ga3+‐radiolabelling and positron emission tomography/computed tomography (PET) imaging of PSMA expression in vivo. We herein report the formulation of [68Ga]Ga‐PSMA‐617 into a ME ≤40 nm including its evaluation for improved cellular toxicity and in vivo biodistribution. The [68Ga]Ga‐PSMA‐617‐ME was tested in vitro for its cytotoxicity to HEK293 and PC3 cells. [68Ga]Ga‐PSMA‐617‐ME was administered intravenously in BALB/c mice followed by microPET/computed tomography (CT) imaging and ex vivo biodistribution determination. [68Ga]Ga‐PSMA‐617‐ME indicated negligible cellular toxicity at different concentrations. A statistically higher tolerance towards the [68Ga]Ga‐PSMA‐617‐ME occurred at 0.125 mg/mL by HEK293 cells compared with PC3 cells. The biodistribution in wild‐type BALB/C mice showed the highest amounts of radioactivity (%ID/g) presented in the kidneys (31%) followed by the small intestine (10%) and stomach (9%); the lowest uptake was seen in the brain (0.5%). The incorporation of [68Ga]Ga‐PSMA‐617 into ME was successfully demonstrated and resulted in a stable nontoxic formulation as evaluated by in vitro and in vivo means

Introduction Non-invasive imaging techniques (especially single-photon emission tomography and positron emission tomography) apply several RGD-based imaging ligands developed during a vast number of preclinical and clinical investigations. The RGD (Arg-Gly-Asp) sequence is a binding moiety for a large selection of adhesive extracellular matrix and cell surface proteins. Since the first identification of this sequence as the shortest sequence required for recognition in fibronectin during the 1980s, fundamental research regarding the molecular mechanisms of integrin action have paved the way for development of several pharmaceuticals and radiopharmaceuticals with clinical applications. Ligands recognizing RGD may be developed for use in the monitoring of these interactions (benign or pathological). Although RGD-based molecular imaging has been actively investigated for oncological purposes, their utilization towards non-oncology applications remains relatively under-exploited. Methods and Scope This review highlights the new non-oncologic applications of RGD-based tracers (with the focus on single-photon emission tomography and positron emission tomography). The focus is on the last 10 years of scientific literature (2009–2020). It is proposed that these imaging agents will be used for off-label indications that may provide options for disease monitoring where there are no approved tracers available, for instance Crohn’s disease or osteoporosis. Fundamental science investigations have made progress in elucidating the involvement of integrin in various diseases not pertaining to oncology. Furthermore, RGD-based radiopharmaceuticals have been evaluated extensively for safety during clinical evaluations of various natures. Conclusion Clinical translation of non-oncological applications for RGD-based radiopharmaceuticals and other imaging tracers without going through time-consuming extensive development is therefore highly plausible

Ubiquicidin is an antimicrobial peptide with great potential for nuclear imaging of infectious diseases, as its cationic-rich fragment TGRAKRRMQYNRR (UBI) has been functionalized with NOTA to allow complexation to 68Ga (68Ga-NOTA-UBI). We herein assess the cytotoxicity and radiation dosimetry for 68Ga-NOTA-UBI and a first-in-human evaluation to diagnose infectious processes. Methods: Cytotoxicity was evaluated in green monkey kidney epithelial (Vero) cells and MT-4 leukocytes. Tracer susceptibility was studied in vitro using different bacterial and fungal strains. PET/CT-based biodistribution, pharmacokinetics, and radiation dosimetry were performed on nonhuman primates. Two healthy volunteers and 3 patients with suspected infection underwent 68Ga-NOTA-UBI PET/CT imaging. Results: Negligible cytotoxicity was determined for NOTA-UBI. 68Ga-NOTA-UBI showed moderate blood clearance (29-min half-life) and predominant renal clearance in nonhuman primates. Human radiation dose estimates indicated the bladder wall as the dose-critical tissue (185 μSv/MBq), followed by the kidneys (23 μSv/MBq). The total absorbed body dose was low (

Bacterial infections are a major concern in the human health sector due to poor diagnosis and development of multidrug-resistant strains. PET/CT provides a means for the non-invasive detection and localization of the infectious foci; however, the radiotracers available are either cumbersome to prepare or their exact contribution toward the imaging is not yet established. Human antimicrobial peptides are of interest for development as PET radiotracers as they are an integral component of the immune system, non-immunogenic toward the recipient, and show selectivity toward pathogens such as bacteria. Herein we report on the potential of LL37, a human cathelicidin antimicrobial peptide, as a radiotracer for bacterial imaging. Bifunctional chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid was utilized to functionalize the antimicrobial peptide, which in turn was capable of chelating gallium. The synthesized nat Ga-CDP1 showed bacterial selectivity and low affinity toward hepatic cells, which are favorable characteristics for further preclinical application.

This review describes the usefulness of in silico design approaches in the design of new radiopharmaceuticals, especially peptide-based radiotracers (including peptidomimetics). Although not part of the standard arsenal utilized during radiopharmaceutical design, the use of in silico strategies is steadily increasing in the field of radiochemistry as it contributes to a more rational and scientific approach. The development of new peptide-based radiopharmaceuticals as well as a short introduction to suitable computational approaches are provided in this review. The first section comprises a concise overview of the three most useful computeraided drug design strategies used, namely i) a Ligand-based Approach (LBDD) using pharmacophore modelling, ii) a Structure-based Design Approach (SBDD) using molecular docking strategies and iii) Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) predictions. The second section summarizes the challenges connected to these computer-aided techniques and discusses successful applications of in silico radiopharmaceutical design in peptide-based radiopharmaceutical development, thereby improving the clinical procedure in Nuclear Medicine. Finally, the advances and future potential of in silico modelling as a design strategy is highlighted.

Safety and efficacy are of concern in developing new compounds. There is a paucity on the changes made by new compounds on inflammatory cytokines in combination with oxidative stress markers. Cytokines are potential markers of drug safety, focusing on cardiovascular, neurologic, and respiratory functions. In addition oxidative stress markers may indicate the impact of drugs on physiological processes. According to literature, a dysregulation of cytokines can be indicative of chronic inflammation. There is no formal reference of normal ranges of inflammatory markers. By the establishment of a baseline for preclinical safety studies, the effects of new compounds on cytokines can be quantified. When cancer cells were then exposed to an anti-cancer compound, the anti-oxidative enzymes' activity increased. Oxidative stress plays an important role in the regulation of physiological processes. The aim of this study was to determine the changes in the cytokines and anti-oxidant enzymes in the renal and hepatic systems in vivo (xenograft rats) after treatment with radiolabeled compounds (confidential, under development). Tissue was collected from xenografted RNU rats, from a control group and two radiolabeled compound exposed groups. The cytokines were analyzed using a CBA Flow Cytometry cytokine assay. Oxidative stress markers analyzed was intracellular reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), protein carbonyls (PC), and lipid peroxidation (malondialdehyde, (MDA)). There were changes in the cytokines and oxidative stress markers post-exposure to radiolabeled compounds. In the kidneys, the copper-chelate (Cu-c) increased the pro- and anti-inflammatory cytokines (55% & 35%), where Pd-c decreased both (30% & 39%). In contrast liver cytokines for the Cu-c group (19 & 41%) decreased but increased for Pd-c (45 & 84%). In the kidneys, ROS was lower in Cu-c groups and showed an increase for Pd-c. The SOD levels in the kidneys was increased (30%) for Cu-c and decreased (20%) for Pd-c. A 120% increase for Cu-c and 328% decrease for Pd-c was seen for SOD in the liver. The CAT levels in the kidneys were elevated for Cu-c (45%) and Pd-c (67%) compared to the control. In contrast CAT levels in the liver showed a 50% decrease in both Cu-c and Pd-c. The Cu-c group was responsible for more protein damage, whereas Pd-c was responsible for more lipid peroxidation. A relationship between the anti-oxidant markers and the cytokines was seen. This suggest that cytokines in combination with oxidative stress markers may be used as indicators for drug safety

Microemulsions (MEs) are reported to improve the efficacy of a drug, minimise side effects and toxicity of the encapsulated compound. MEs are hypothesized to aid in making the encapsulated compound, which has been incorporated within the ME, safe in vivo due to reduced side effects and toxicity to the kidneys and other non-target organs. This study aimed to contribute to knowledge on the toxicity of the ME delivery system and ME containing [68Ga]Ga-PSMA-11 with specific reference to intravenous tail vein administration. ME and [68Ga]Ga-PSMA-11-ME were synthesized by homogenisation under high temperature and a dose of 150 μl per mouse was administered intravenously in 10 healthy male BALB/c mice. The mice were monitored and evaluated for 14 days for clinical signs, mortality, body weights, and gross necropsy findings. The mice were euthanized after the respective 14-day period followed by isolation of respective organs and blood samples. Blood test results included assessment of alanine transaminase, aspartate transaminase, total protein, urea, creatinine and serum lipid levels. There were no abnormal changes observed in the body weight, coat condition, respiration, mobility and behaviour of any of the mice during the study. The survival rate was 10/10 mice (100%) after 14 days. None of the treatment groups showed any treatment related toxicity to either ME or [68Ga]Ga-PSMA-11-ME. Blood testing showed that liver and kidney function was in the normal range in both mice groups. This treatment regimen of the administered ME and [68Ga]Ga-PSMA-11-ME concentration caused no acute toxicity to small rodents but further investigations are required in larger animal models to justify the safety of [68Ga]Ga-PSMA-11-ME injections into humans

The cathelicidin-derived peptide (CDP1) is a human antimicrobial peptide that preferentially targets bacterial membranes in response to infection. CDP1 was functionalised with NODAGA and DOTA for complexation with gallium-68 to evaluate its potential as an infection imaging tracer. The synthesis of [68Ga]Ga–NODAGA–CDP1 and [68Ga]Ga–DOTA–CDP1 were optimised for pH, molarity, incubation time and temperature, and product purification. The integrity and protein binding were investigated employing [68Ga]GaCl3 and [68Ga]Ga–DOTA–TATE as internal references. [68Ga]Ga–NODAGA–CDP1 displayed good labelling properties with higher product yield compared to [68Ga]Ga–DOTA–CDP1. In contrast, [68Ga]Ga–DOTA–CDP1 showed better stability and is the preferred candidate for an in vivo investigation.

Purpose Nuclear imaging is an important preclinical research tool to study infectious diseases in vivo and could be extended to investigate complex aspects of malaria infections. As such, we report for the first time successful radiolabeling of a novel antibody specific to Plasmodium-infected erythrocytes (IIIB6), its in vitro assessment and molecular imaging in nude mice. Procedures In vitro confocal microscopy was used to determine the stage-specificity of Plasmodium-infected erythrocytes recognised by IIIB6. To enable micro-positron emission tomography (PET)/X-ray computed tomography (CT) imaging, IIIB6 was conjugated to Bz-DFO-NCS and subsequently radiolabeled with zirconium-89. Healthy nude mice were injected with [89Zr]IIIB6, and pharmacokinetics and organ uptake were monitored over 24 h. This was followed by post-mortem animal dissection to determine the biodistribution of [89Zr]IIIB6. Results IIIB6 recognised all the relevant stages of Plasmodium falciparum-infected erythrocytes (trophozoites, schizonts and gametocytes) that are responsible for severe malaria pathology. [89Zr]IIIB6-radiolabeling yields were efficient at 84–89 %. Blood pool imaging analysis indicated a pharmacological half-life of 9.6 ± 2.5 h for [89Zr]IIIB6. The highest standard uptake values were determined at 2–6 h in the liver followed by the spleen, kidneys, heart, stomach and lung, respectively. Minimal activity was present in muscle and bone tissues. Conclusion In vitro characterization of IIIB6 and pharmacokinetic characterization of [89Zr]IIIB6 revealed that this antibody has potential for future use in Plasmodium-infected mouse models to study malaria in a preclinical in vivo setting with PET/CT imaging

Graphical abstract, Highlights • Acute administration of 2000 mg/kg of the Pheroid® delivery system was tolerated upon intravenous administration in BALB/c mice and Sprague-Dawley rats. • Oral administration was tolerated in both acute toxicity evaluation (14-days post single dose administration) and during chronic administration (90-days dosing). • No mutagenicity was present during the Ames assay. • A statistically significant increase in creatinine levels in the sub-chronic female treatment group was observed, however no treatment related pathology was identified during histopathology. • This evaluation did not identify any risk factors present for toxicity during oral or intravenous administration of the tested formulations during acute or repeated dosing., The Pheroid® drug delivery system is now on the threshold of progressing into human clinical trials for various patented pharmaceutical applications and a systematic investigation of its toxicological properties in vitro and in vivo is thus a priority. Colloidal dispersions (nano- and microemulsions) demonstrate the ability to be adapted to accommodate either lipophilic, hydrophilic or amphiphilic drug molecules. The colloidal dispersions investigated during this evaluation has a general size of 200 nm - 2 μm, a zeta-potential of -25 mV and the main ingredient was ethyl esters of essential fatty acids. The Ames mutagenicity assay was performed on selected Salmonella thyphimurium strains TA98, TA100 and TA102. The Ames assay included S9 metabolic activation and no mutagenicity was present during the assay. The effect of acute and subchronic administration on a biological system was investigated in two species of rodent (BALB/c mice and Sprague-Dawley rats). Observations focused on the physical condition, blood biochemical analysis and the haematological profiles. Gross necropsy was performed on all the test animals. Organ weights followed by histopathology of selected organ tissues were recorded. During the acute evaluation animals showed tolerance of the maximum prescribed dose of 2000 mg/kg (according to OECD guidelines) in two rodent species after intravenous administration (absolute bioavaibility). The oral formulation was tolerated without incidents in both acute and subchronic studies. Although valuable baseline safety data was obtained regarding the Pheroid® system, future studies with the entrapped active pharmaceutical ingredients is necessary to provide a definitive safety profile.

PhD (Pharmaceutics), North-West University, Potchefstroom Campus It has been reported that microemulsion (ME) delivery systems provide an opportunity to enhance the bioavailability and efficacy of a therapeutic agent whilst minimising side effects. The prostate-specific membrane antigen (PSMA) targeting agents PSMA-11 and PSMA-617, which accumulate in prostate tumours, allows for [68Ga]Ga3+-radiolabelling and PET imaging of PSMA-expression in vivo. Radiolabelled [68Ga]Ga-PSMA-617 can be encapsulated in a ME delivery system which is hypothesized to enhance its pharmacokinetic properties. This study investigated the synthesis of [68Ga]Ga-PSMA-617 and [68Ga]Ga-PSMA-617 contained within a ME, the toxicity profile, and microPET/CT imaging and biodistribution in PC3 tumour xenograft male BALB/c mice. [68Ga]Ga-PSMA-617 was synthesized in a combined solid phase and solution chemistry strategy. The formulation of [68Ga]Ga-PSMA-617 into a ME was then evaluated for in vitro and in vivo toxicity and biodistribution. The cytotoxicity of [68Ga]Ga-PSMA-617-ME was tested in HEK293 and PC3 cells. [68Ga]Ga-PSMA-617-ME indicated negligible cellular toxicity at different concentrations. HEK293 cells showed a statistically higher tolerance towards the [68Ga]Ga-PSMA-617-ME compared to PC3 cells. [68Ga]Ga-PSMA-617 and [68Ga]Ga-PSMA-617-ME was administered intravenously in BALB/c mice with or without PC3-tumours followed by microPET/CT imaging and ex vivo biodistribution determination. The ex vivo biodistribution in PC3-tumour bearing BALB/c mice showed the highest amounts of [68Ga]Ga-PSMA-617 radioactivity accumulation in the kidneys and the lowest uptake was seen in the brain. Both the [68Ga]Ga-PSMA-617 and [68Ga]Ga-PSMA-617-ME followed an expected clearance profile for small-sized polar radiopharmaceuticals, with predominant renal clearance. The ME did alter the biodistribution pattern of [68Ga]Ga-PSMA-617 but maintained distribution to the kidneys, albeit at statistically significant higher levels. Similarly, encapsulation in the ME may have resulted in delayed uptake into tumours as can be seen from the higher blood pool values. The incorporation of [68Ga]Ga-PSMA-617 into ME was successfully demonstrated and resulted in a stable non-toxic formulation as evaluated by in vitro and in vivo means. Both the [68Ga]Ga-PSMA-617 and [68Ga]Ga-PSMA-617-ME showed enterohepatic metabolism of [68Ga]Ga-PSMA-617. Doctoral

The aim of this study was to establish the in vivo uptake and tissue distribution of 99mTc-MDP-encapsulated Solid Lipid Nanoparticles (SLNs) post administration. Radioactive 99mTc-MDP encapsulated into SLNs was administered to rats to trace their biodistribution through imaging and ex vivo studies. As expected IV injected 99mTc-MDP exhibited predominant visual bone uptake and a high localisation of particles in the kidneys (3.87%ID/g) followed by bone (2.66%ID/g). IV administered 99mTc-MDP encapsulated by SLN showed similar uptake than 99mTc-MDP. Orally administrated 99mTc-MDP showed no uptake in any organs except the GI-tract while orally administered 99mTc-MDP-SLN showed distinct transfer of 99mTc-MDP from the GI tract with measurable levels in the kidneys and bone.

MSc (Applied Radiation Science), North-West University, Mafikeng Campus "Abstract not copied" Masters

Introduction Drug delivery systems are entities designed to alter the biological behaviour of the pharmaceutical active ingredients that they carry in order to afford more beneficial biodistribution and safety profiles. Many problems currently faced by the field of nuclear medicine (e.g. developing new theranostic agents, utilizing multimodal imaging platforms and providing targeted delivery) can be facilitated by applying drug delivery systems to radiopharmaceuticals that have been proven successful in other medical fields. This review describes the advancements being made towards this goal. Areas covered All aspects of drug delivery systems (liposomes, nanoparticles, microspheres) in the field of nuclear medicine are discussed. Only systems with foreseen or confirmed clinical applications in nuclear medicine are discussed, not instances where nuclear imaging is merely a tool to evaluate the biodistribution of novel delivery technologies. Conclusion Great advancements have been made with the development of novel systems incorporating nuclear entities in drug delivery systems, with the possibility of reshaping the nuclear medicine landscape. Nonetheless, translation from preclinical evaluations to clinical use is lacking and serious investment needs to be made towards this goal.

MSc (Pharmaceutics), North-West University, Potchefstroom Campus Pheroid® is a lipid-based drug delivery system which has been shown to entrap, protect and deliver hydrophilic, hydrophobic and amphiphilic compounds across biological membranes. As a result Pheroid® has the advantage of increasing gastrointestinal absorption of drugs. Pheroid® could provide a means of oral delivery for drugs such as 99mTc-MDP (99mTechnetium methylene diphosphonate), an intravenously administered radiotracer used during bone scans. Oral administration of Pheroid® 99mTc-MDP was shown in rats. This suggested Pheroid® may enhance bioavailability of radiopharmaceuticals potentially allowing an alternative to intravenous administration. Thus increasing safety for medical staff as well as patient compliance. Due to instability and loss of activity, formulations containing radiotracers are prepared shortly before administration. For clinical applications an optimised formulation with99mTc-MDP entrapment/association in Pheroid® within 2-6 hrs. is required. Formulation parameters of Pheroid® were systematically altered and the effects studied using particle size distribution and ?-potential as indication of stability. Formulations showing early stability were selected for further investigation. Light microscopy was used to confirm morphology while reflectance microscopy was used to qualitatively assess entrapment within or association of Sn-MDP with Pheroid®. Formulations displaying suitable entrapment were selected for quantitative determination of entrapment efficiencies utilizing a novel methodology. Entrapment efficiency was measured by incubating Pheroid-99mTc-MDP formulations on hydroxyapatite (HAP), as in vitro bone model. In the absence of metabolic function any amount of 99mTc-MDP unable to adsorb to the synthetic hydroxyapatite media may be considered to be associated with/entrapped within Pheroid® structures. Although stable formulations are necessary for pharmaceuticals, this study highlighted inadequacies of standard stability measurements as an indication of entrapment efficiency. Insight into the effect of certain formulation parameters on formulation stability as well as an alternative method for determining entrapment efficiencies for certain classes of compounds in Pheroid® formulations are highlighted. Two formulations were identified for further investigation for clinical application: Pheroid® vesicles with 99mTc-MDP added to aqueous phase (N2O-H2O) before preparation and Pre-prepared Pheroid® vesicles; 99mTc-MDP added 4 days after formulation. The latter having the advantage of ease of preparation within clinical settings. All experiments were conducted in triplicate and one way analysis of variance (ANOVA) was used to determined reproducibility, applying a significance level α = 0.05. Masters

Colloidal suspensions of 14 nm gold nanoparticles (AuNPs) were repeatedly administered intravenously at three dose levels (0.9, 9 and 90 µg) to male Sprague Dawley rats weekly for 7 weeks, followed by a 14-day washout period. After sacrificing, the amount of gold was quantified in the liver, lungs, spleen, skeleton and carcass using neutron activation analysis (NAA). During the study, pre- and post (24 h) administration blood samples were collected from both the test and control groups, the latter which received an equal injection volume of normal saline. General health indicators were monitored together with markers of kidney and liver damage for acute and subchronic toxicity assessment. Histopathological assessments were done on the heart, kidneys, liver, lungs and spleen to assess any morphological changes as a result of the exposure to AuNPs. The mass measurements of all the groups showed a steady increase with no signs of overt toxicity. The liver had the highest amount of gold (µg) per gram of tissue after 56 days followed by the spleen, lungs, skeleton and carcass. Markers of kidney and liver damage showed similar trends between the pre and post samples within each group and across groups. The histopathological examination also showed no hepatotoxicity and nephrotoxicity. There was accumulation of Au in tissues after repeated dosing, albeit with no observable overt toxicity, kidney or liver damage.

MSc. (Applied Radiation Science and Technology), North-West University, Mafikeng Campus, 2016 Patients with inoperable neuro-endocrine tumours (NETs) often have symptoms (i.e. diarrhea...) that decrease their quality of life. Targeted radionuclide therapy (TRT) can be used to increase the quality of life for these patients by relieving symptoms and suppressing tumour growth. For NETs, ¹⁷⁷Lu-[DOTA0, Tyr3] (a radiolabelled somatostatin analogue) is used as TRT. The organs at risk for this TRT are the kidneys and bone marrow, therefore, dosimetry should be performed in these patients to avoid side effects of over exposure (

Radiopharmaceuticals containing the motive tripeptide arginyl-glycyl-asparatic acid (RGD) are known to target ανβ3 integrins during tumor angiogenesis. A more generic kit radiolabeling procedure accommodating Ga-68 from different generators was developed for NOTA-RGD and evaluated for its versatile use and safety in subsequent in vivo applications. The [68Ga]NOTA-RGD kit was further verified for its expected biodistribution and pharmacokinetics in nonhuman primates and its clinical sensitivity to detect solitary pulmonary nodules (SPN) in cancer patients. Single vial kits containing 28–56 nmol of NOTA-cyclo-Arg-Gly-Asp-d-Tyr-Lys (NOTA-RGD) and sodium acetate trihydrate buffer were formulated. Versatility of the NOTA-RGD radiolabeling performance and adaption to a TiO2- and a SnO2-based generator type, characterization and long-term storage stability of the kits were carried out. The blood clearance and urine recovery kinetics as well as the image-guided biodistribution of [68Ga]NOTA-RGD was studied in a vervet monkey model. [68Ga]NOTA-RGD kits were further tested clinically to target solitary pulmonary nodules. The kits could be successfully formulated warranting integrity over 3–4 months with a good [68Ga]NOTA-RGD radiolabeling performance (radiochemical purity >95 %, decay corrected yield 76–94 %, specific activity of 8.8–37.9 GBq/μmol) The kits met all quality requirements to be further tested in vivo. [68Ga]NOTA-RGD cleared rapidly from blood and was majorly excreted via the renal route. The liver, spleen, heart and intestines showed initial uptake with steadily declining tissue activity concentration over time. In addition, the [68Ga]NOTA-RGD kit allowed for delineation of SPN from non-malignant lung tissue in humans. A more versatile radiolabeling procedure using kit-formulated NOTA-RGD and different generator types was achieved. The uncompromised in vivo behavior and efficient targeting of SPN warrants further investigations on the clinical relevance of [68Ga]NOTA-RGD derivatives to implement initial guidelines and management of patients, with regard to integrin targeted imaging.

This paper describes a five-step synthesis of a carbon-14-labelled pyrazole compound (11). A total of 2.96 MBq of 11 was obtained with the specific activity of 2242.4 MBq/mmol. The radiochemical purity was >99%, and the overall radiochemical yield was 60% based on the [14C6] 4-bromoaniline starting material. Biodistribution results showed that the radiotracer (administrated orally) has a high accumulation in the small intestine, large intestine and liver of both non-infected and tuberculosis (TB)-infected mice. Therefore, this suggests that compound 11 undergoes hepatobiliary clearance. The compound under investigation has been found to be slowly released from the liver between 2 and 8 h. The study revealed that 11 has no affinity for TB cells

MSc (Applied Radiation Science and Technology), North-West University, Mafikeng Campus This study was carried out in an effort to verify ⁸⁹Zr as a new safe and effective nuclide for immuno-PET imaging. In recent years, immuno-PET imaging has been of increasing importance in cancer diagnostics due to its rare abilities. This diagnostic tool has the ability to selectively target tumours thus allowing patients with cancers associated with poor prognosis to be identified in early stages of the disease. One of the cancers associated with poor prognosis is the epithelial ovarian cancer. At present, epithelial ovarian cancer is the fifth leading form of cancer resulting in deaths of women in the United States of America and possibly the rest of the world. The high mortality rate associated with epithelial ovarian cancer is the basis of this research because it shows that there is a need to develop effective tracers. The stability and the in vivo robustness of the ⁸⁹Zr-DFO chelator system as part of potential immuno-PET radiopharmaceuticals was investigated by means of potentiometry and computer simulation of blood plasma. Glass electrode potentiometry was used to measure formation constants of the complexation of Zr⁴⁺ with DFO and the competing blood plasma ligands. This made the construction of the blood plasma model possible because the formation constants that were attained were used in ECCLES blood plasma model to evaluate the competitive stability of the ⁸⁹Zr-DFO chelator system against biological metal ions and ligands. The results of the ECCLES blood plasma model showed that 99.7 % of Zr⁴⁺ ions will not dissociate from the ⁸⁹Zr-DFO complex when administered at a concentration of 8.5 x 10⁻⁵ mol.dm⁻³.This was a positive result showing that almost all of the metal ions will reach the targeted area, however, the ligand on the other hand proved to be less stable resulting in a 10 % stability. The model showed that 88.6 % of the ligand will dissociate to form a complex with Fe³⁺ thus leading to a significant mobilization of the metal ion in the blood plasma. Masters

The antimalarial compound MMV390048 ([14C]-11) was labeled with carbon-14 isotope via a 3-step synthesis. It was obtained in a 15.5% radiochemical overall yield from carbon-14 labeled methyl iodide with a radiochemical purity of >99%. After single oral administration of [14C]-11 to albino and pigmented rats its tissue distribution profile was studied. Tissue distribution results showed high local exposure in the GI tract and excretory organs but low exposure of all other tissues. The radioactivity uptake was higher in the eyes of the pigmented rats than in the eyes of the albino rats at all-time points. The highest accumulation reached in the eyes of the pigmented rats was 0.46% at 6 hours. However, these levels are still very low as compared to the other organs studied. There was very little radioactivity from MMV390048 ([14C]-11) present in the skin of both the albino and pigmented rats. The results obtained are supportive of further development of MMV390048 as a potential antimalarial compound

Therapeutic radiopharmaceuticals for bone pain palliation play an important role in providing quality of life for cancer patients with metastatic bone cancer. There is currently interest in using 177Lu in many radiopharmaceuticals, since 177Lu has favorable nuclear decay characteristics. The usefulness of 177Lu complexed to ethylenediaminetetramethylene phosphonic acid (EDTMP) has been demonstrated in clinical trials. This study seeks to understand the in vivo chemistry of the [177Lu]Lu–EDTMP complex in blood plasma. Complex formation constants of Lu(III) and Yb(III) were measured by glass electrode potentiometry at 25 °C and I = 150 mM. The computer simulations indicated that [Lu(EDTMP)]5− and [Lu(EDTMP)H]4− are the major Lu(III) complexes formed in blood plasma. These results explains why [177Lu]Lu–EDTMP survives competition by other blood plasma metal ions and is delivered to the metastases. A thermodynamic blood plasma simulation revealed that Lu(III) is practically quantitatively complexed to EDTMP in vivo.

Prostate-specific membrane antigen (PSMA), a type II glycoprotein, is highly expressed in almost all prostate cancers. By playing such a universal role in the disease, PSMA provides a target for diagnostic imaging of prostate cancer using positron emission tomography/computed tomography (PET/CT). The PSMA-targeting ligand Glu-NH-CO-NH-Lys-(Ahx)-HBED-CC (DKFZ-PSMA-11) has superior imaging properties and allows for highly-specific complexation of the generator-based radioisotope Gallium-68 ((68)Ga). However, only module-based radiolabeling procedures are currently available. This study intended to develop a single vial kit solution to radiolabel buffered DKFZ-PSMA-11 with (68)Ga. A (68)Ge/(68)Ga-generator was utilized to yield (68)GaCl3 and major aspects of the kit development were assessed, such as radiolabeling performance, quality assurance, and stability. The final product was injected into patients with prostate cancer for PET/CT imaging and the kit performance was evaluated on the basis of the expected biodistribution, lesion detection, and dose optimization. Kits containing 5 nmol DKFZ-PSMA-11 showed rapid, quantitative (68)Ga-complexation and all quality measurements met the release criteria for human application. The increased precursor content did not compromise the ability of (68)Ga-DKFZ-PSMA-11 PET/CT to detect primary prostate cancer and its advanced lymphatic- and metastatic lesions. The (68)Ga-DKFZ-PSMA-11 kit is a robust, ready-to-use diagnostic agent in prostate cancer with high diagnostic performance.

Gold nanoparticles (AuNPs) have shown great potential for use in nanomedicine and nanotechnologies due to their ease of synthesis and functionalization. However, their apparent biocompatibility and biodistribution is still a matter of intense debate due to the lack of clear safety data. To investigate the biodistribution of AuNPs, monodisperse 14-nm dual-radiolabeled [14C]citrate-coated [198Au]AuNPs were synthesized and their physico-chemical characteristics compared to those of non-radiolabeled AuNPs synthesized by the same method. The dual-radiolabeled AuNPs were administered to rats by oral or intravenous routes. After 24 h, the amounts of Au core and citrate surface coating were quantified using gamma spectroscopy for 198Au and liquid scintillation for the 14C. The Au core and citrate surface coating had different biodistribution profiles in the organs/tissues analyzed, and no oral absorption was observed. We conclude that the different components of the AuNPs system, in this case the Au core and citrate surface coating, did not remain intact, resulting in the different distribution profiles observed. A better understanding of the biodistribution profiles of other surface attachments or cargo of AuNPs in relation to the Au core is required to successfully use AuNPs as drug delivery vehicles South African Nanotechnology Initiative

Noninvasive imaging is a powerful tool for early diagnosis and monitoring of various disease processes, such as infections. An alarming shortage of infection-selective radiopharmaceuticals exists for overcoming the diagnostic limitations with unspecific tracers such as67/68Ga-citrate or18F-FDG. We report here TBIA101, an antimicrobial peptide derivative that was conjugated to DOTA and radiolabeled with68Ga for a subsequentin vitroassessment andin vivoinfection imaging usingEscherichia coli-bearing mice by targeting bacterial lipopolysaccharides with PET/CT. Following DOTA-conjugation, the compound was verified for its cytotoxic and bacterial binding behaviour and compound stability, followed by68Gallium-radiolabeling.µPET/CT using68Ga-DOTA-TBIA101 was employed to detect muscularE. coli-infection in BALB/c mice, as warranted by thein vitroresults.68Ga-DOTA-TBIA101-PET detectedE. coli-infected muscle tissue (SUV = 1.3–2.4) > noninfected thighs(P=0.322)> forearm muscles(P=0.092)> background(P=0.021)in the same animal. Normalization of the infected thigh muscle to reference tissue showed a ratio of 3.0 ± 0.8 and a ratio of 2.3 ± 0.6 compared to the identical healthy tissue. The majority of the activity was cleared by renal excretion. The latter findings warrant further preclinical imaging studies of greater depth, as the DOTA-conjugation did not compromise the TBIA101’s capacity as targeting vector.