Radiochemical synthesis and in vivo evaluation of [18F]AZ11637326: An agonist probe for the α7 nicotinic acetylcholine receptor

Hayden T. Ravert, Peter Dorff, Catherine Foss, Ronnie Mease, Hong Fan, Christopher R. Holmquist, Eifion Phillips, Dennis J. McCarthy, J. Richard Heys, Daniel Holt, Yuchuan Wang, Christopher J. Endres, Robert F Dannals, Martin Gilbert Pomper

Research output: Contribution to journalArticle

Abstract

Introduction: The alpha-7 nicotinic acetylcholine receptor (α7 nAChR) is key in brain communication and has been implicated in the pathophysiology of diseases of the central nervous system. A positron-emitting radioligand targeting the α7 nAChR would enable better understanding of a variety of neuropsychiatric illnesses, including schizophrenia and Alzheimer's disease, and could enhance the development of new drugs for these and other conditions. We describe our attempt to synthesize an α7 nAChR-selective radiotracer for positron emission tomography (PET). Methods: We prepared the high-affinity (Kd=0.2 nM) α7 nAChR agonist, 5'-(2-[18F]fluorophenyl)spiro[1-azabicyclo-[2.2.2]octane]-3,2'-(3'H)furo[2,3-b]pyridine, [18F]AZ11637326, in two steps, a nucleophilic fluorination followed by decarbonylation. We studied [18F]AZ11637326 in rodents, including mice lacking α7 nAChR, and in non-human primates. Results: [18F]AZ11637326 was synthesized in a non-decay-corrected radiochemical yield of 3% from the end of synthesis (90min) with a radiochemical purity >90% and average specific radioactivity of 140GBq/μmol (3,781mCi/μmol). Modest rodent brain uptake was observed (2-5% injected dose per gram of tissue, depending on specific activity), with studies comparing CD-1 and α7 nAChR null mice indicating an element of target-specific binding. Blocking studies in non-human primates did not reveal specific binding within the brain. Conclusion: Despite the high affinity and target selectivity of AZ11637326 for α7 nAChR in vitro and encouraging rodent studies, receptor-mediated binding could not be demonstrated in non-human primates. Further structural optimization of compounds of this class will be required for them to serve as suitable radiotracers for PET.

Original languageEnglish (US)
Pages (from-to)731-739
Number of pages9
JournalNuclear Medicine and Biology
Volume40
Issue number6
DOIs
StatePublished - Aug 2013

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Nicotinic Receptors
Primates
Rodentia
Positron-Emission Tomography
Brain
Cholinergic Agonists
Halogenation
Central Nervous System Diseases
5'-(2-fluorophenyl)-spiro(1-azabicyclo(2.2.2)octane-3,2'(3'H)-furo(2,3-b)pyridine)
Radioactivity
Schizophrenia
Alzheimer Disease
Communication
Electrons
Pharmaceutical Preparations

Keywords

  • Brain
  • Molecular imaging
  • PET
  • Radiopharmaceutical
  • Spirofuropyridine

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

Cite this

Radiochemical synthesis and in vivo evaluation of [18F]AZ11637326 : An agonist probe for the α7 nicotinic acetylcholine receptor. / Ravert, Hayden T.; Dorff, Peter; Foss, Catherine; Mease, Ronnie; Fan, Hong; Holmquist, Christopher R.; Phillips, Eifion; McCarthy, Dennis J.; Heys, J. Richard; Holt, Daniel; Wang, Yuchuan; Endres, Christopher J.; Dannals, Robert F; Pomper, Martin Gilbert.

In: Nuclear Medicine and Biology, Vol. 40, No. 6, 08.2013, p. 731-739.

Research output: Contribution to journalArticle

Ravert, Hayden T. ; Dorff, Peter ; Foss, Catherine ; Mease, Ronnie ; Fan, Hong ; Holmquist, Christopher R. ; Phillips, Eifion ; McCarthy, Dennis J. ; Heys, J. Richard ; Holt, Daniel ; Wang, Yuchuan ; Endres, Christopher J. ; Dannals, Robert F ; Pomper, Martin Gilbert. / Radiochemical synthesis and in vivo evaluation of [18F]AZ11637326 : An agonist probe for the α7 nicotinic acetylcholine receptor. In: Nuclear Medicine and Biology. 2013 ; Vol. 40, No. 6. pp. 731-739.
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abstract = "Introduction: The alpha-7 nicotinic acetylcholine receptor (α7 nAChR) is key in brain communication and has been implicated in the pathophysiology of diseases of the central nervous system. A positron-emitting radioligand targeting the α7 nAChR would enable better understanding of a variety of neuropsychiatric illnesses, including schizophrenia and Alzheimer's disease, and could enhance the development of new drugs for these and other conditions. We describe our attempt to synthesize an α7 nAChR-selective radiotracer for positron emission tomography (PET). Methods: We prepared the high-affinity (Kd=0.2 nM) α7 nAChR agonist, 5'-(2-[18F]fluorophenyl)spiro[1-azabicyclo-[2.2.2]octane]-3,2'-(3'H)furo[2,3-b]pyridine, [18F]AZ11637326, in two steps, a nucleophilic fluorination followed by decarbonylation. We studied [18F]AZ11637326 in rodents, including mice lacking α7 nAChR, and in non-human primates. Results: [18F]AZ11637326 was synthesized in a non-decay-corrected radiochemical yield of 3{\%} from the end of synthesis (90min) with a radiochemical purity >90{\%} and average specific radioactivity of 140GBq/μmol (3,781mCi/μmol). Modest rodent brain uptake was observed (2-5{\%} injected dose per gram of tissue, depending on specific activity), with studies comparing CD-1 and α7 nAChR null mice indicating an element of target-specific binding. Blocking studies in non-human primates did not reveal specific binding within the brain. Conclusion: Despite the high affinity and target selectivity of AZ11637326 for α7 nAChR in vitro and encouraging rodent studies, receptor-mediated binding could not be demonstrated in non-human primates. Further structural optimization of compounds of this class will be required for them to serve as suitable radiotracers for PET.",
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T2 - An agonist probe for the α7 nicotinic acetylcholine receptor

AU - Ravert, Hayden T.

AU - Dorff, Peter

AU - Foss, Catherine

AU - Mease, Ronnie

AU - Fan, Hong

AU - Holmquist, Christopher R.

AU - Phillips, Eifion

AU - McCarthy, Dennis J.

AU - Heys, J. Richard

AU - Holt, Daniel

AU - Wang, Yuchuan

AU - Endres, Christopher J.

AU - Dannals, Robert F

AU - Pomper, Martin Gilbert

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N2 - Introduction: The alpha-7 nicotinic acetylcholine receptor (α7 nAChR) is key in brain communication and has been implicated in the pathophysiology of diseases of the central nervous system. A positron-emitting radioligand targeting the α7 nAChR would enable better understanding of a variety of neuropsychiatric illnesses, including schizophrenia and Alzheimer's disease, and could enhance the development of new drugs for these and other conditions. We describe our attempt to synthesize an α7 nAChR-selective radiotracer for positron emission tomography (PET). Methods: We prepared the high-affinity (Kd=0.2 nM) α7 nAChR agonist, 5'-(2-[18F]fluorophenyl)spiro[1-azabicyclo-[2.2.2]octane]-3,2'-(3'H)furo[2,3-b]pyridine, [18F]AZ11637326, in two steps, a nucleophilic fluorination followed by decarbonylation. We studied [18F]AZ11637326 in rodents, including mice lacking α7 nAChR, and in non-human primates. Results: [18F]AZ11637326 was synthesized in a non-decay-corrected radiochemical yield of 3% from the end of synthesis (90min) with a radiochemical purity >90% and average specific radioactivity of 140GBq/μmol (3,781mCi/μmol). Modest rodent brain uptake was observed (2-5% injected dose per gram of tissue, depending on specific activity), with studies comparing CD-1 and α7 nAChR null mice indicating an element of target-specific binding. Blocking studies in non-human primates did not reveal specific binding within the brain. Conclusion: Despite the high affinity and target selectivity of AZ11637326 for α7 nAChR in vitro and encouraging rodent studies, receptor-mediated binding could not be demonstrated in non-human primates. Further structural optimization of compounds of this class will be required for them to serve as suitable radiotracers for PET.

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