{"id":{"repo_id":"sask","oai_identifier":"oai:harvest.usask.ca:10388/16939"},"canonical_url":"https://search.dev.ndltd.org/etd/sask/oai:harvest.usask.ca:10388/16939","repository":{"repo_id":"sask","name":"University of Saskatchewan","base_url":"https://harvest.usask.ca/server/oai/request"},"display":{"title":"Synthesis of fluorinated cannabinoid derivatives; Towards PET radiotracers for imaging the cannabinoid receptor","abstract":"Efforts toward understanding the endocannabinoid system, which is comprised of cannabinoid receptors and endogenous ligands, have rapidly expanded in recent years. The endocannabinoid system can modulate the activity of other neurotransmitters through the type 1 cannabinoid receptor (CB1R) which is highly expressed in the human brain1,2. Defects in CB1R expression or endocannabinoid transmission have been associated with several neuropsychiatric disorders thus establishing CB1R as a potential drug target or biomarker of disease3. However, tools to study the function of the endocannabinoid system, especially in vivo, are limited4. Therefore, functional imaging techniques, such as positron emission tomography (PET), may be useful for understanding the complex role of the endocannabinoid system in animals and humans. Our major focus was to prepare novel fluorinated analogs of tetrahydrocannabinol (THC)-type, cannabidiol (CBD)-type, cannabicyclol (CBL)-type, and cannabichromene- (CBC)-type plant cannabinoids from Cannabis sativa as PET tracer candidates. Synthetic routes were developed leading to several novel fluorinated cannabinoids, and their respective precursors, that could be efficiently labeled with 18F for in vivo PET imaging studies. Before radiolabeling chemistry, the biological activity of each fluorinated cannabinoid towards CB1R was assessed in cell models (and in some cases rodents) successfully identifying several promising ligands that represent PET tracer candidates. The adverse psychotropic effects associated with CB1R orthosteric agonists remain a challenge to the development of novel cannabinoid-derived therapeutics leading to the development of GAT211 as CB1R-positive allosteric modulators (PAMs)5,6. In the second part of this project, we embarked on modifying structural features of GAT211. Biological assays in vitro and in vivo were used to determine if the fluorinated cannabinoid derivatives behaved as partial agonists and/or PAMs. Four derivatives of the cannabinoids that exhibited potent biological activity with high binding affinity to CB1R were subsequently labeled with 18F for biodistribution, and preliminary microPET imaging studies in mice. Dynamic PET/CT imaging of the radiolabeled THC analog shows that this radiotracer readily entered the brain within 1-minute post-injection and was slowly cleared from the brain. To demonstrate specific binding of the radiolabeled cannabinoids to CB1R, control mice were injected with the CB1R antagonist rimonabant (1 mg/kg) prior to administration of the radiotracer. In animals treated with rimonabant, radiotracer uptake in specific areas of the brain was reduced demonstrating CB1R-selective binding. This study underscores the dual utility of these novel cannabinoids as potential CB1R modulators and as PET tracers.","abstract_html":"Efforts toward understanding the endocannabinoid system, which is comprised of cannabinoid receptors and endogenous ligands, have rapidly expanded in recent years. The endocannabinoid system can modulate the activity of other neurotransmitters through the type 1 cannabinoid receptor (CB1R) which is highly expressed in the human brain1,2. Defects in CB1R expression or endocannabinoid transmission have been associated with several neuropsychiatric disorders thus establishing CB1R as a potential drug target or biomarker of disease3. However, tools to study the function of the endocannabinoid system, especially in vivo, are limited4. Therefore, functional imaging techniques, such as positron emission tomography (PET), may be useful for understanding the complex role of the endocannabinoid system in animals and humans. Our major focus was to prepare novel fluorinated analogs of tetrahydrocannabinol (THC)-type, cannabidiol (CBD)-type, cannabicyclol (CBL)-type, and cannabichromene- (CBC)-type plant cannabinoids from Cannabis sativa as PET tracer candidates. Synthetic routes were developed leading to several novel fluorinated cannabinoids, and their respective precursors, that could be efficiently labeled with 18F for in vivo PET imaging studies. Before radiolabeling chemistry, the biological activity of each fluorinated cannabinoid towards CB1R was assessed in cell models (and in some cases rodents) successfully identifying several promising ligands that represent PET tracer candidates. The adverse psychotropic effects associated with CB1R orthosteric agonists remain a challenge to the development of novel cannabinoid-derived therapeutics leading to the development of GAT211 as CB1R-positive allosteric modulators (PAMs)5,6. In the second part of this project, we embarked on modifying structural features of GAT211. Biological assays in vitro and in vivo were used to determine if the fluorinated cannabinoid derivatives behaved as partial agonists and/or PAMs. Four derivatives of the cannabinoids that exhibited potent biological activity with high binding affinity to CB1R were subsequently labeled with 18F for biodistribution, and preliminary microPET imaging studies in mice. Dynamic PET/CT imaging of the radiolabeled THC analog shows that this radiotracer readily entered the brain within 1-minute post-injection and was slowly cleared from the brain. To demonstrate specific binding of the radiolabeled cannabinoids to CB1R, control mice were injected with the CB1R antagonist rimonabant (1 mg/kg) prior to administration of the radiotracer. In animals treated with rimonabant, radiotracer uptake in specific areas of the brain was reduced demonstrating CB1R-selective binding. This study underscores the dual utility of these novel cannabinoids as potential CB1R modulators and as PET tracers.","abstract_has_math":false,"creators":["Orji, Placid Nnamdi"],"institution":"University of Saskatchewan","degree_name":"Doctor of Philosophy (Ph.D.)","degree_level":"Doctoral","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":[],"advisors":["Laprairie, Robert","Phenix, Christopher"],"committee_chairs":[],"committee_members":["Palmer, David","Abrams, Suzanne","Howland, John","Gravel, Michel","Kostikov, Alexey"],"year":null,"date_issued":"","date_published":null,"updated_at":"2026-07-24T04:27:20Z","subjects":["endocannabinoid system","cannabinoid receptors","endogenous ligands","CB1R","neurotransmitters","neuropsychiatric disorders","drug target","biomarker","functional imaging","positron emission tomography","PET","fluorinated analogs","tetrahydrocannabinol","THC","cannabidiol","CBD","cannabicyclol","CBL","cannabichromene","CBC","Cannabis sativa","PET tracers","radiolabeling","18F","in vivo imaging","biological activity","cell models","rodents","ligands","psychotropic effects","orthosteric agonists","GAT211","positive allosteric modulators","PAMs","structural modification","biological assays","partial agonists","biodistribution","microPET imaging","dynamic PET/CT imaging","radiotracer","brain uptake","rimonabant","CB1R antagonist","selective binding","CB1R modulators"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/10388/16939","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Laprairie, Robert","Phenix, Christopher"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Palmer, David","Abrams, Suzanne","Howland, John","Gravel, Michel","Kostikov, Alexey"]},{"key":"dc:creator","label":"Author","values":["Orji, Placid Nnamdi"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-05-20T21:01:25Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (Ph.D.)"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Saskatchewan"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["endocannabinoid system","cannabinoid receptors","endogenous ligands","CB1R","neurotransmitters","neuropsychiatric disorders","drug target","biomarker","functional imaging","positron emission tomography","PET","fluorinated analogs","tetrahydrocannabinol","THC","cannabidiol","CBD","cannabicyclol","CBL","cannabichromene","CBC","Cannabis sativa","PET tracers","radiolabeling","18F","in vivo imaging","biological activity","cell models","rodents","ligands","psychotropic effects","orthosteric agonists","GAT211","positive allosteric modulators","PAMs","structural modification","biological assays","partial agonists","biodistribution","microPET imaging","dynamic PET/CT imaging","radiotracer","brain uptake","rimonabant","CB1R antagonist","selective binding","CB1R modulators"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10388/16939"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Efforts toward understanding the endocannabinoid system, which is comprised of cannabinoid receptors and endogenous ligands, have rapidly expanded in recent years. The endocannabinoid system can modulate the activity of other neurotransmitters through the type 1 cannabinoid receptor (CB1R) which is highly expressed in the human brain1,2. Defects in CB1R expression or endocannabinoid transmission have been associated with several neuropsychiatric disorders thus establishing CB1R as a potential drug target or biomarker of disease3. However, tools to study the function of the endocannabinoid system, especially in vivo, are limited4. Therefore, functional imaging techniques, such as positron emission tomography (PET), may be useful for understanding the complex role of the endocannabinoid system in animals and humans. Our major focus was to prepare novel fluorinated analogs of tetrahydrocannabinol (THC)-type, cannabidiol (CBD)-type, cannabicyclol (CBL)-type, and cannabichromene- (CBC)-type plant cannabinoids from Cannabis sativa as PET tracer candidates. Synthetic routes were developed leading to several novel fluorinated cannabinoids, and their respective precursors, that could be efficiently labeled with 18F for in vivo PET imaging studies. Before radiolabeling chemistry, the biological activity of each fluorinated cannabinoid towards CB1R was assessed in cell models (and in some cases rodents) successfully identifying several promising ligands that represent PET tracer candidates. The adverse psychotropic effects associated with CB1R orthosteric agonists remain a challenge to the development of novel cannabinoid-derived therapeutics leading to the development of GAT211 as CB1R-positive allosteric modulators (PAMs)5,6. In the second part of this project, we embarked on modifying structural features of GAT211. Biological assays in vitro and in vivo were used to determine if the fluorinated cannabinoid derivatives behaved as partial agonists and/or PAMs. Four derivatives of the cannabinoids that exhibited potent biological activity with high binding affinity to CB1R were subsequently labeled with 18F for biodistribution, and preliminary microPET imaging studies in mice. Dynamic PET/CT imaging of the radiolabeled THC analog shows that this radiotracer readily entered the brain within 1-minute post-injection and was slowly cleared from the brain. To demonstrate specific binding of the radiolabeled cannabinoids to CB1R, control mice were injected with the CB1R antagonist rimonabant (1 mg/kg) prior to administration of the radiotracer. In animals treated with rimonabant, radiotracer uptake in specific areas of the brain was reduced demonstrating CB1R-selective binding. This study underscores the dual utility of these novel cannabinoids as potential CB1R modulators and as PET tracers."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Synthesis of fluorinated cannabinoid derivatives; Towards PET radiotracers for imaging the cannabinoid receptor"]}]}],"canonical_facts":{"dc:contributor.advisor":["Laprairie, Robert","Phenix, Christopher"],"dc:contributor.committeemember":["Palmer, David","Abrams, Suzanne","Howland, John","Gravel, Michel","Kostikov, Alexey"],"dc:creator":["Orji, Placid Nnamdi"],"dc:date.accessioned":["2025-05-20T21:01:25Z"],"dc:description.abstract":["Efforts toward understanding the endocannabinoid system, which is comprised of cannabinoid receptors and endogenous ligands, have rapidly expanded in recent years. The endocannabinoid system can modulate the activity of other neurotransmitters through the type 1 cannabinoid receptor (CB1R) which is highly expressed in the human brain1,2. Defects in CB1R expression or endocannabinoid transmission have been associated with several neuropsychiatric disorders thus establishing CB1R as a potential drug target or biomarker of disease3. However, tools to study the function of the endocannabinoid system, especially in vivo, are limited4. Therefore, functional imaging techniques, such as positron emission tomography (PET), may be useful for understanding the complex role of the endocannabinoid system in animals and humans. Our major focus was to prepare novel fluorinated analogs of tetrahydrocannabinol (THC)-type, cannabidiol (CBD)-type, cannabicyclol (CBL)-type, and cannabichromene- (CBC)-type plant cannabinoids from Cannabis sativa as PET tracer candidates. Synthetic routes were developed leading to several novel fluorinated cannabinoids, and their respective precursors, that could be efficiently labeled with 18F for in vivo PET imaging studies. Before radiolabeling chemistry, the biological activity of each fluorinated cannabinoid towards CB1R was assessed in cell models (and in some cases rodents) successfully identifying several promising ligands that represent PET tracer candidates. The adverse psychotropic effects associated with CB1R orthosteric agonists remain a challenge to the development of novel cannabinoid-derived therapeutics leading to the development of GAT211 as CB1R-positive allosteric modulators (PAMs)5,6. In the second part of this project, we embarked on modifying structural features of GAT211. Biological assays in vitro and in vivo were used to determine if the fluorinated cannabinoid derivatives behaved as partial agonists and/or PAMs. Four derivatives of the cannabinoids that exhibited potent biological activity with high binding affinity to CB1R were subsequently labeled with 18F for biodistribution, and preliminary microPET imaging studies in mice. Dynamic PET/CT imaging of the radiolabeled THC analog shows that this radiotracer readily entered the brain within 1-minute post-injection and was slowly cleared from the brain. To demonstrate specific binding of the radiolabeled cannabinoids to CB1R, control mice were injected with the CB1R antagonist rimonabant (1 mg/kg) prior to administration of the radiotracer. In animals treated with rimonabant, radiotracer uptake in specific areas of the brain was reduced demonstrating CB1R-selective binding. This study underscores the dual utility of these novel cannabinoids as potential CB1R modulators and as PET tracers."],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://hdl.handle.net/10388/16939"],"dc:language.iso":["en"],"dc:subject":["endocannabinoid system","cannabinoid receptors","endogenous ligands","CB1R","neurotransmitters","neuropsychiatric disorders","drug target","biomarker","functional imaging","positron emission tomography","PET","fluorinated analogs","tetrahydrocannabinol","THC","cannabidiol","CBD","cannabicyclol","CBL","cannabichromene","CBC","Cannabis sativa","PET tracers","radiolabeling","18F","in vivo imaging","biological activity","cell models","rodents","ligands","psychotropic effects","orthosteric agonists","GAT211","positive allosteric modulators","PAMs","structural modification","biological assays","partial agonists","biodistribution","microPET imaging","dynamic PET/CT imaging","radiotracer","brain uptake","rimonabant","CB1R antagonist","selective binding","CB1R modulators"],"dc:title":["Synthesis of fluorinated cannabinoid derivatives; Towards PET radiotracers for imaging the cannabinoid receptor"],"dc:type":["Thesis"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Doctoral"],"thesis:degree_name":["Doctor of Philosophy (Ph.D.)"],"thesis:institution_name":["University of Saskatchewan"]},"updated_at":"2026-07-24T04:27:20Z"}