Väitös (kliininen fysiologia ja isotooppilääketiede): MSc Obada Alzghool
Aika
27.2.2024 klo 12.00 - 16.00
MSc Obada Alzghool esittää väitöskirjansa ”Preclinical Development of Radiopharmaceuticals for Alzheimer’s Disease – Biological Evaluation of (S)-[18F]THK5117 and [11C]SMW139 PET Tracers in the APP/PS1-21 Mouse Model of Alzheimer’s Disease” julkisesti tarkastettavaksi Turun yliopistossa tiistaina 27.02.2024 klo 12.00 (Turun yliopisto, Medisiina C, Osmo Järvi -sali, Kiinamyllynkatu 10, Turku).
Vastaväittäjänä toimii apulaisprofessori Mikael Palner (University of Southern Denmark, Tanska) ja kustoksena dosentti Merja Haaparanta-Solin (Turun yliopisto). Tilaisuus on englanninkielinen. Väitöksen alana on kliininen fysiologia ja isotooppilääketiede.
Väitöskirja yliopiston julkaisuarkistossa: https://urn.fi/URN:ISBN:978-951-29-9604-9
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Tiivistelmä väitöstutkimuksesta:
Alzheimers disease affects millions of people globally. The pathological changes inside the brains of patients with AD involve the accumulation of ß-amyloid peptides (Aß), hyperphosphorylated tau (p-tau) protein aggregates, and neuroinflammation. These processes lead to progressive damage to brain neurons, resulting in a decline in memory and mental abilities over time.
Positron emission tomography (PET) imaging enables detecting and monitoring pathological processes in living subjects through PET tracers. The applications of PET imaging have expanded from research to drug development and are increasingly being used to diagnose AD. To fully leverage the role of PET, it is necessary to develop PET tracers with improved target binding characteristics and pharmacokinetic properties. This advancement could be particularly significant in enabling early diagnosis of AD. The preclinical evaluation of new PET tracers in AD animal models is a crucial phase towards the clinical use of new PET tracers.
The aim of this thesis was to conduct a preclinical evaluation of two PET tracers, (S)-[18F]THK5117 and [11C]SMW139, which target p-tau aggregates and neuroinflammatory reactive glia, respectively, in the APP/PS1-21 mouse model of AD. The studies conducted in this thesis, namely I-III, focused on evaluating the binding characteristics, pharmacokinetic properties, and metabolism of these PET tracers.
In the APP/PS1-21 mice, (S)-[18F]THK5117 binding associated with Aß aggregates and MAO-B enzyme, but not p-tau aggregates. [11C]SMW139 longitudinal uptake did not increase with ageing, despite the ongoing neuroinflammation in APP/PS1-21 mice. Histological evaluation of imaging targets (p-tau for (S)-[18F]THK5117, and P2X7 receptor for [11C]SMW139) associated well with the imaging results. (S)-[18F]THK5117 demonstrated suitable pharmacokinetic properties without brain-penetrating radiometabolites. On the contrary, [11C]SMW139 had fast and unfavourable metabolism for in vivo imaging, with multiple brain-penetrating radiometabolites and substantial binding to plasma proteins.
In conclusion, tracers preclinical evaluation performed in the APP/PS1-21 mouse model of AD showed that binding of (S)-[18F]THK5117 in the brain is mainly non-specific, and binding of [11C]SMW139 is insufficient. Overall, these findings suggest that the in vivo PET imaging of p-tau aggregates with (S)-[18F]THK5117 and reactive glia with [11C]SMW139 in mice has significant limitations, which restrict their preclinical and possibly clinical use.
Vastaväittäjänä toimii apulaisprofessori Mikael Palner (University of Southern Denmark, Tanska) ja kustoksena dosentti Merja Haaparanta-Solin (Turun yliopisto). Tilaisuus on englanninkielinen. Väitöksen alana on kliininen fysiologia ja isotooppilääketiede.
Väitöskirja yliopiston julkaisuarkistossa: https://urn.fi/URN:ISBN:978-951-29-9604-9
***
Tiivistelmä väitöstutkimuksesta:
Alzheimers disease affects millions of people globally. The pathological changes inside the brains of patients with AD involve the accumulation of ß-amyloid peptides (Aß), hyperphosphorylated tau (p-tau) protein aggregates, and neuroinflammation. These processes lead to progressive damage to brain neurons, resulting in a decline in memory and mental abilities over time.
Positron emission tomography (PET) imaging enables detecting and monitoring pathological processes in living subjects through PET tracers. The applications of PET imaging have expanded from research to drug development and are increasingly being used to diagnose AD. To fully leverage the role of PET, it is necessary to develop PET tracers with improved target binding characteristics and pharmacokinetic properties. This advancement could be particularly significant in enabling early diagnosis of AD. The preclinical evaluation of new PET tracers in AD animal models is a crucial phase towards the clinical use of new PET tracers.
The aim of this thesis was to conduct a preclinical evaluation of two PET tracers, (S)-[18F]THK5117 and [11C]SMW139, which target p-tau aggregates and neuroinflammatory reactive glia, respectively, in the APP/PS1-21 mouse model of AD. The studies conducted in this thesis, namely I-III, focused on evaluating the binding characteristics, pharmacokinetic properties, and metabolism of these PET tracers.
In the APP/PS1-21 mice, (S)-[18F]THK5117 binding associated with Aß aggregates and MAO-B enzyme, but not p-tau aggregates. [11C]SMW139 longitudinal uptake did not increase with ageing, despite the ongoing neuroinflammation in APP/PS1-21 mice. Histological evaluation of imaging targets (p-tau for (S)-[18F]THK5117, and P2X7 receptor for [11C]SMW139) associated well with the imaging results. (S)-[18F]THK5117 demonstrated suitable pharmacokinetic properties without brain-penetrating radiometabolites. On the contrary, [11C]SMW139 had fast and unfavourable metabolism for in vivo imaging, with multiple brain-penetrating radiometabolites and substantial binding to plasma proteins.
In conclusion, tracers preclinical evaluation performed in the APP/PS1-21 mouse model of AD showed that binding of (S)-[18F]THK5117 in the brain is mainly non-specific, and binding of [11C]SMW139 is insufficient. Overall, these findings suggest that the in vivo PET imaging of p-tau aggregates with (S)-[18F]THK5117 and reactive glia with [11C]SMW139 in mice has significant limitations, which restrict their preclinical and possibly clinical use.
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