Development of rapid multistep carbon-11 radiosynthesis of the myeloperoxidase inhibitor AZD3241 to assess brain exposure by PET microdosing.
Peter Johnström, Linda Bergman, Katarina Varnäs, Jonas Malmquist, Christer Halldin, Lars Farde
Nuclear medicine and biology June 2015 DOI: 10.1016/j.nucmedbio.2015.02.001 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical radiochemistry and PET imaging study Peer reviewed |
|---|---|
| Sample size | 3 |
| Population | Cynomolgus monkeys (non-human primates) |
| Topics | Microdosing |
| Keywords | Azd3241 Carbon-11 Cyanation Myeloperoxidase PET |
| Key points | The myeloperoxidase inhibitor AZD3241 was successfully labeled with carbon-11 in a four-step procedure, and PET microdosing in three cynomolgus monkeys showed rapid, homogeneous brain uptake reaching 1.9 to 2.6 percent of injected radioactivity within 1.5 minutes, which the authors say confirms adequate brain exposure to support phase 2a studies in patients. |
Abstract
The myeloperoxidase inhibitor AZD3241 has been selected as a candidate drug currently being developed to delay progression in patients with neurodegenerative brain disorders. Part of the decision tree for translation of AZD3241 into clinical studies included the need for assessment of brain exposure in non-human primates by PET microdosing. For that purpose a rapid multistep method for (11)C-labeling of AZD3241 was developed. AZD3241 was labeled in the thio-carbonyl position starting from [(11)C]potassium cyanide in a 4-step procedure using microwave assisted heating. In the first step [(11)C]potassium cyanide was converted to [(11)C]potassium thiocyanate followed by reaction with benzoyl chloride to yield benzoyl [(11)C]isothiocyanate. The benzoyl [(11)C]isothiocyanate was subsequently reacted with the precursor ethyl 3-(2-isopropoxyethylamino)-1H-pyrrole-2-carboxylate and the formed intermediate underwent a base catalyzed cyclization to obtain [(11)C]AZD3241 in the final step. To assess [(11)C]AZD3241 brain exposure PET measurements were performed in three cynomolgus monkeys. [(11)C]AZD3241 was produced in good and reproducible radiochemical yield 710 ± 294 MBq (mean ± SD, n = 7). Total time of synthesis was 60 min from end of bombardment. The specific radioactivity was 9 ± 4GBq/μmol and the radiochemical purity was >98%. Following iv administration of [(11)C]AZD3241 there was a rapid presence of radioactivity in brain in each of the three monkeys. The distribution of [(11)C]AZD3241 to brain was fast and a Cmax of 1.9 to 2.6% of the injected radioactivity was observed within 1.5 min. [(11)C]AZD3241 was homogeneously distributed in brain. The MPO inhibitor AZD3241 was successfully labeled with carbon-11 in a challenging 4-step procedure in good radiochemical yield allowing PET microdosing studies in cynomolgus monkey. [(11)C]AZD3241 rapidly entered brain and confirmed adequate brain exposure to support translation of AZD3241 to phase 2a studies in patients.
Comparable studies
Other preclinical and animal studies on microdosing, most cited first.
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| Repeated microdoses of LSD do not alter anxiety or boldness in zebrafish. Zebrafish (Danio rerio) | 2024 | Experimental study | |
| Application of microarray patches for the transdermal administration of psychedelic drugs in micro-doses. Excised neonatal porcine skin and rats | 2025 | Experimental study | |
| Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing Paired sensitive and resistant cancer cell lines, AML cell lines, and 10 viably... | 2018 | Preclinical cell line study with a pilot retrospective analysis of primary patient samples | n = 10 |
Citations in the library
Cited by 2
- Phase 0/microdosing approaches: time for mainstream application in drug development? Nature Reviews Drug Discovery September 8, 2020
- Phase 0, Including Microdosing Approaches: Applying the Three Rs and Increasing the Efficiency of Human Drug Development Alternatives to Laboratory Animals December 1, 2018