EXPLORING CHARACTERISTICS OF VACCINATED DOGS THAT FAIL TO ACHIEVE AN ADEQUATE LEVEL OF RABIES VIRUS NEUTRALIZING ANTIBODIES

Master of Public HealthPublic Health Interdepartmental ProgramMajor Professor Not ListedThis study provides additional findings that could potentially have implications for current and future guidelines as they pertain to pet travel, vaccination campaigns, and exposure recommendations. Furthermore, the study provides insight into additional research needed within the area of rabies serology specifically as it pertains to the influence of breed or dog size, primary versus anamnestic responses to vaccination, and smaller sampling intervals to determine the initial detection of immunocompetence

[18F]Fluoroform - a versatile building block for PET tracer synthesis

Fluorine-18 (half-life: 110 min) is a popular radionuclide for positron emission tomography (PET), a functional imaging technique that non-invasively visualizes biochemical processes in vivo. It can be introduced into tracer molecules via fluorine-18 labelled building blocks. [18F]Fluoroform is a building block that has received much interest in recent years and is used to introduce radioactive CF3 groups into the tracer molecules. However, shortcomings of [18F]fluoroform, such as the low molar activities typically obtained and the limited 18F-trifluoromethylation strategies available, hampered its use in PET tracer synthesis so far. The aim of this thesis was therefore to address these shortcomings and develop [18F]fluoroform into a useful building block for PET tracer synthesis. In Chapter 1 a general introduction into the topic is provided, discussing the basic concepts of positron emission tomography, different radionuclides and radiofluorination strategies. Furthermore, the building block [18F]fluoroform is introduced. Chapter 2 gives a comprehensive overview of the fluorine-18 labelled building blocks used in PET tracer synthesis from 2010-2016. The overview comprises aromatic and aliphatic building blocks, including [18F]fluoroform. Chapter 3 reports the development of a new method to obtain reactive [18F]fluoride omitting the commonly used azeotropic drying procedures. For this method, hydrated [18F]fluoride was reacted with a bistriflate precursor to form gaseous [18F]triflyl fluoride. The [18F]triflyl fluoride was distilled into a dry organic solvent containing base and cryptand, where it was converted to free [18F]fluoride. Besides being fast, reliable, and high-yielding, this novel method offers high flexibility in the subsequent radiofluorination reaction, particularly enabling the reduction of base and cryptand amounts. Chapter 4 describes the optimization of the [18F]fluoroform synthesis towards a high molar activity procedure. Stability studies with the labelling precursor difluoroiodomethane showed that difluoroiodomethane was unstable under the basic radiofluorination conditions, probably causing the low molar activity typically observed with [18F]fluoroform. By reducing the amount of base and cryptand 100-fold compared to standard radiofluorination conditions the stability of difluoroiodomethane and the molar activity of [18F]fluoroform could be drastically improved. Radiochemical yields of around 40% and molar activities close to 100 GBq/µmol were obtained. The optimized synthesis procedure was automated on a commercially available synthesizer to enhance applicability and facilitate the use in other PET centres. In chapter 5 a novel precursor for the synthesis of [18F]fluoroform is presented, 1-(difluoromethyl)-3-methyl-4-phenyl-1H-1,2,3-triazol-3-ium triflate. It was investigated whether this precursor could provide [18F]fluoroform with even higher molar activities than difluoroiodomethane. It was found that also for this precursor reduction of base and cryptand amounts led to increased precursor stability and high molar activities of [18F]fluoroform. Especially in the automated synthesis the triazolium precursor provided [18F]fluoroform with some of the highest molar activities observed so far (~150 GBq/µmol). Chapter 6 reports the first synthesis and application of fluorine-18 labelled Ruppert-Prakash reagent ([18F]Me3SiCF3) as 18F-trifluoromethylation agent. [18F]Me3SiCF3 was synthesized by reaction of [18F]fluoroform with trimethylsilyl chloride and obtained with radiochemical yields of 85-95% and radiochemical purities of >95%. It was reacted in a simple model reaction with a range of aromatic aldehydes and ketones and proved good reactivity as well as a complementary substrate scope to previously reported methods. Chapter 7 describes the development and evaluation of the new tracer [18F]cinacalcet for the localization of overactive parathyroid glands for surgery. [18F]Cinacalcet was synthesized using the optimized [18F]fluoroform procedure described in chapter 4, followed by aromatic 18F-trifluoromethylation of a boronic acid precursor. [18F]Cinacalcet was obtained with an overall radiochemical yield of 8±4% and a molar activity of 40±11 GBq/µmol within 1 hour (n=7,dc). A biodistribution and metabolite study was performed in healthy rats, showing decent uptake in the parathyroid glands and fast blood metabolism. Chapter 8 gives a short summary and outlook

Recent Developments in Carbon-11 Chemistry and Applications for First-In-Human PET Studies

Positron emission tomography (PET) is a molecular imaging technique that makes use of radiolabelled molecules for in vivo evaluation. Carbon-11 is a frequently used radionuclide for the labelling of small molecule PET tracers and can be incorporated into organic molecules without changing their physicochemical properties. While the short half-life of carbon-11 (11C; t½ = 20.4 min) offers other advantages for imaging including multiple PET scans in the same subject on the same day, its use is limited to facilities that have an on-site cyclotron, and the radiochemical transformations are consequently more restrictive. Many researchers have embraced this challenge by discovering novel carbon-11 radiolabelling methodologies to broaden the synthetic versatility of this radionuclide. This review presents new carbon-11 building blocks and radiochemical transformations as well as PET tracers that have advanced to first-in-human studies over the past five years

Recent Developments in Carbon-11 Chemistry and Applications for First-In-Human PET Studies

Positron emission tomography (PET) is a molecular imaging technique that makes use of radiolabelled molecules for in vivo evaluation. Carbon-11 is a frequently used radionuclide for the labelling of small molecule PET tracers and can be incorporated into organic molecules without changing their physicochemical properties. While the short half-life of carbon-11 (11C; t½ = 20.4 min) offers other advantages for imaging including multiple PET scans in the same subject on the same day, its use is limited to facilities that have an on-site cyclotron, and the radiochemical transformations are consequently more restrictive. Many researchers have embraced this challenge by discovering novel carbon-11 radiolabelling methodologies to broaden the synthetic versatility of this radionuclide. This review presents new carbon-11 building blocks and radiochemical transformations as well as PET tracers that have advanced to first-in-human studies over the past five years

Recent Developments in Carbon-11 Chemistry and Applications for First-In-Human PET Studies

Positron emission tomography (PET) is a molecular imaging technique that makes use of radiolabelled molecules for in vivo evaluation. Carbon-11 is a frequently used radionuclide for the labelling of small molecule PET tracers and can be incorporated into organic molecules without changing their physicochemical properties. While the short half-life of carbon-11 (11C; t½ = 20.4 min) offers other advantages for imaging including multiple PET scans in the same subject on the same day, its use is limited to facilities that have an on-site cyclotron, and the radiochemical transformations are consequently more restrictive. Many researchers have embraced this challenge by discovering novel carbon-11 radiolabelling methodologies to broaden the synthetic versatility of this radionuclide. This review presents new carbon-11 building blocks and radiochemical transformations as well as PET tracers that have advanced to first-in-human studies over the past five years.</jats:p

Risk factors for inadequate antibody response to primary rabies vaccination in dogs under one year of age.

Ensuring the adequacy of response to rabies vaccination in dogs is important, particularly in the context of pet travel. Few studies have examined the factors associated with dogs' failure to achieve an adequate antibody titer after vaccination (0.5 IU/ml). This study evaluated rabies antibody titers in dogs after primary vaccination. Dogs under one year of age whose serum was submitted to a reference laboratory for routine diagnostics, and which had no prior documented history of vaccination were enrolled (n = 8,011). Geometric mean titers (GMT) were calculated and univariate analysis was performed to assess factors associated with failure to achieve 0.5 IU/mL. Dogs vaccinated at >16 weeks of age had a significantly higher GMT compared to dogs vaccinated at a younger age (1.64 IU/ml, 1.57-1.72, ANOVA p < 0.01). There was no statistical difference in GMT between dogs vaccinated <12 weeks and dogs vaccinated 12-16 weeks (1.22 IU/ml and 1.21 IU/ml). The majority of dogs failed to reach an adequate titer within the first 3 days of primary vaccination; failure rates were also high if the interval from vaccination to titer check was greater than 90 days. Over 90% of dogs that failed primary vaccination were able to achieve adequate titers after booster vaccination. The ideal timing for blood draw is 8-30 days after primary vaccination. In the event of a failure, most dogs will achieve an adequate serologic response upon a repeat titer (in the absence of booster vaccination). Booster vaccination after failure provided the highest probability of an acceptable titer

Synthesis of [18F]Fluoroform with High Molar Activity

Fluoroform is an interesting motif for the isotopologue labelling of biologically active compounds with fluorine-18 for PET imaging. However, so far the building block [18F]fluoroform and consequently the [18F]trifluoromethylated products suffered from low molar activities ranging from 0.1 to 30 GBq/µmol due to isotopic dilution under the strongly basic standard radiofluorination conditions. In this article the synthesis of high molar activity [18F]fluoroform is described. By implementing a recently reported novel radiofluorination reagent, [18F]triflyl fluoride, the concentration of base-cryptand complex in the reaction could be reduced 100-fold compared to standard radiofluorination conditions and molar activities close to 100 GBq/µmol (at end of [18F]fluoroform synthesis) could be obtained, enabling the imaging of low density receptors. Furthermore, an automated procedure was developed on the commercially available NEPTIS® perform synthesizer to provide access of high molar activity [18F]fluoroform to other PET centres

Fluorine-18 labelled Ruppert–Prakash reagent ([¹⁸F]Me₃SiCF₃) for the synthesis of ¹⁸F-trifluoromethylated compounds

The radiolabelling of Ruppert–Prakash reagent with fluorine-18 was developed and applied in the [18F]trifluoromethylation of benzaldehydes, acetophenones and benzophenones.</p