Protein kinase B (PKB or Akt), is a serine/threonine protein kinase. Akt, containing three isoforms Akt1, Akt2, and Akt3, is a downstream target for phosphoinositide 3-kinase (PI3K), a critical regulator of cell growth and transformation. The mammalian target of rapamycin (mTOR) is a key component of PI3K pathway and is also a central regulator of cell growth. The PI3K/Akt/mTOR pathway is an intracellular signaling pathway that is involved in several cell functions including growth, proliferation, apoptosis and autophagy, and is among the most commonly activated pathways in human cancers. Akt is a pivotal node in the PI3K/Akt/mTOR pathway and has emerged as an attractive target for cancer therapeutics, and several Akt inhibitors are currently in human clinical trials. Among these, GDC-0068 {(R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one} is a potent Akt inhibitor with IC50 5, 18 and 8 nM for Akt1, Akt2 and Akt3, respectively. Me-GDC-0068 {(R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1-one} is a derivative of GDC-0068 with similar potency, IC50 18, 31 and 28 nM for Akt1, Akt2 and Akt3, respectively. Akt has become an interesting target for cancer imaging, however, no specific imaging agents have been developed so far. Carbon-11 and fluorine-18 labeled GDC-0068 compounds may serve as new probes for the biomedical imaging technique PET, and enable non-invasive monitoring of the enzyme Akt in cancers. To radiolabel therapeutic agents as diagnostic agents for imaging of Akt and monitoring of therapeutic efficacy of Akt inhibitors, we have designed and synthesized [11C]Me-GDC-0068 {(R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropyl([11C]methyl)amino)propan-1-one}. The standard Me-GDC-0068 was synthesized from GDC-0068 with 37% formaldehyde and NaBH(OAc)3 under DIPEA in 77% yield. The tracer [11C]Me-GDC-0068 was prepared from GDC-0068 with [11C]CH3OTf under NaH through N-[11C]methylation and isolated by HPLC combined with SPE in 30-45% radiochemical yield based on [11C]CO2 and decay corrected to EOB. The radiosynthesis was performed in a home-built automated 11C-radiosynthesis module. The radiochemical purity was &gt;99%, and specific activity at EOB was 370-1110 GBq/µmol.

Fully automated synthesis of [11C]Me-GDC-0068 as a PET tracer for imaging of Akt in cancers

253rd National Meeting (2017)

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