Development of rapid multistep carbon-11 radiosynthesis of the myeloperoxidase inhibitor AZD3241 to assess brain exposure by PET microdosing

Johnström, Peter; Bergman, Linda; Varnäs, Katarina; Malmquist, Jonas; Halldin, Christer; Farde, Lars

doi:10.1016/j.nucmedbio.2015.02.001

Cited by 20 publications

(12 citation statements)

References 19 publications

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“…The low extent of brain exposure for gefitinib in the PET studies is consistent with human clinical experience, lending support to this approach being predictive. Indeed, PET microdosing in nonhuman primates has been used to confirm adequate brain exposure with AZD3241, a drug targeting the CNS to support to the conduct of phase IIa studies in patients (45,46).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

Ballard

Yates

Yang³

et al. 2016

Clinical Cancer Research

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586

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Purpose: Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions.Experimental Design: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632).Results: Osimertinib demonstrated greater penetration of the mouse blood-brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [11 C]osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [11 C]rociletinib and [ 11 C]gefitinib. Early clinical evidence of osimertinib activity in previously treated patients with EGFRm-advanced NSCLC and brain metastases is also reported.Conclusions: Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing.

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Section: Discussionmentioning

confidence: 99%

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

Ballard

Yates

Yang³

et al. 2016

Clinical Cancer Research

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586

482

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“…The development of therapeutics targeting the inflammatory response and pathways demands potent noninvasive methods to detect the efficacy of these emerging drugs. Besides the aforementioned imaging methods to detect MPO activity, a 11 C-labeled MPO inhibitor, [ 11 C]AZD3241, that can enter monkey brains was reported for MPO imaging (43). However, the half-life of 11 C is short (t 1/2 = 20.4 min), and no selectivity and binding affinity of the agent have been revealed.…”

Section: Discussionmentioning

confidence: 99%

An activatable PET imaging radioprobe is a dynamic reporter of myeloperoxidase activity in vivo

Wang

Keliher

Zeller

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Myeloperoxidase (MPO) is a critical proinflammatory enzyme implicated in cardiovascular, neurological, and rheumatological diseases. Emerging therapies targeting inflammation have raised interest in tracking MPO activity in patients. We describe 18 F-MAPP, an activatable MPO activity radioprobe for positron emission tomography (PET) imaging. The activated radioprobe binds to proteins and accumulates at sites of MPO activity. The radioprobe 18 F-MAPP has a short blood half-life, remains stable in plasma, does not demonstrate cytotoxicity, and crosses the intact blood-brain barrier. The 18 F-MAPP imaging detected sites of elevated MPO activity in living mice embedded with human MPO and in mice induced with chemical inflammation or myocardial infarction. The 18 F-MAPP PET imaging noninvasively differentiated varying amounts of MPO activity, competitive inhibition, and MPO deficiency in living animals, confirming specificity and showing that the radioprobe can quantify changes in in vivo MPO activity. The radiosynthesis has been optimized and automated, an important step in translation. These data indicate that 18 F-MAPP is a promising translational candidate to noninvasively monitor MPO activity and inflammation in patients.

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“…Intratarget microdosing MOA/pharmacodynamics 109,110,113,118,132,137 Target localization 9,10,98,100,114,115,117,126,137 PET-microdosing 127,129,134,214 Other imaging methods [120][121][122]135 Intratarget microdosing [15][16][17]123 MOA, mechanism of action; PET, positron emission tomography; PBMCs, peripheral blood mononuclear cells; PBPK, physiologically based pharmacokinetic; SPECT, single-photon emission computed tomography.…”

Section: Metabolites In Safety Testingmentioning

confidence: 99%

“…It can be used for characterization of chemoresistance and prediction of patient response, and can occur and be demonstrated after microdose administration 34,42,49,74,95 . The efficiency of passage across the blood-brain barrier and likewise entry into tumour tissues are compartment-disposition data relevant to a drug's efficacy, and demonstration of lack of passage across the blood-brain barrier may be crucial to concerns about CNS toxicity with drugs whose efficacy targets are elsewhere 9,65,98,115,117 . Other examples from novel drug development include demonstration of the correlation of anti-infective efficacy with pharmacokinetics 110 , localization supportive of or rejecting the MOA 9,114 , accumulation of an amyloid imaging agent in brain regions high in amyloid deposition 100 , development of a novel ligand to a cancer and fibrosis target (αvβ6 integrin) 127 , and glioblastoma penetration and postreceptor modulation 109 .…”

Section: Pd Biomarker And/or Moa Datamentioning

confidence: 99%

Phase 0/microdosing approaches: time for mainstream application in drug development?

Burt¹,

Young

Lee

et al. 2020

Nat Rev Drug Discov

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Phase 0 approaches-which include microdosing-evaluate subtherapeutic exposures of new drugs in first-inhuman studies known as exploratory clinical trials. Recent progress extends phase 0 benefits beyond assessment of pharmacokinetics to include understanding of mechanism of action and pharmacodynamics. Phase 0 approaches have the potential to improve preclinical candidate selection and enable safer, cheaper, quicker and more informed developmental decisions. Here, we discuss phase 0 methods and applications, highlight their advantages over traditional strategies and address concerns related to extrapolation and developmental timelines. Although challenges remain, we propose that phase 0 approaches be at least considered for application in most drug development scenarios.

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Development of rapid multistep carbon-11 radiosynthesis of the myeloperoxidase inhibitor AZD3241 to assess brain exposure by PET microdosing

Cited by 20 publications

References 19 publications

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

An activatable PET imaging radioprobe is a dynamic reporter of myeloperoxidase activity in vivo

Phase 0/microdosing approaches: time for mainstream application in drug development?

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