Radiosynthesis and evaluation of [11C]AG-488, a dual anti-angiogenetic and anti-tubulin PET ligand
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J S Dileep Kumar1, Andrei Molotkov2, Patrick Carberry2
1Area Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, USA; Cyclotron and Radiochemistry Facility, Feinstein Institute for Medical Research, Northwell School of Medicine, Manhasset, USA; Institute of Molecular Medicine, Feinstein Institute for Medical Research, Northwell School of Medicine, Manhasset, USA.
Abstract:
Combinations of antiangiogenic and cytotoxic agents show promising results in the treatment of cancer. However, there is a lack of single agent with both antiangiogenic and cytotoxic activities for clinical application. AG-488 aka FLAG-003 is a novel ligand with established antiangiogenetic properties via activation of receptor thymidine kinase (RTK) and anti-tubulin properties in tumor cells. AG-488 is also reported to reduce tumor volume and prolong survival in preclinical animal models of glioblastoma multiforme, breast cancer and is in clinical stage. Higher expression of RTKs and tubulins is reported in various cancers. This study reveals the development of [11C]AG-488, a high affinity dual target inhibitor binding to RTK and anti-tubulin activities. We rationale that antiangiogenic RTK and anti-tubulin activity of [11C]AG-488 may enhance the tumor to tissue ratio, assisting in cancer drug development. [11C]AG-488 was synthesized in 35 ± 5 % radiochemical yield by radiomethylating the corresponding phenolate using [11C]CH3I. MicroPET studies in mice indicated blood-brain barrier penetration of [11C]AG-488 and retention in the brain. However, blocking studies with antitubulin and RTK agent HD-800 and microtubule depolymerizing agent MPC-6827 show increased binding of [11C]AG-488 in brain. The pattern of tracer binding in blocking conditions is similar to the baseline conditions. The higher binding may be due to the increased plasma uptake of radiotracer or the formation of more free tubulins due to microtubule dynamic instability during the blocking conditions.
Insights
A novel dual-acting cancer therapeutic, [11C]AG-488, targets receptor tyrosine kinases (RTKs) and tubulin, showing potential for improved cancer drug development and imaging. Further studies are needed to clarify its brain retention mechanisms.
Area of Science:
- Oncology
- Radiochemistry
- Pharmacology
Background:
- Combinations of antiangiogenic and cytotoxic agents are effective in cancer treatment, but a single agent with both activities is lacking.
- AG-488 is a novel ligand with demonstrated antiangiogenic (via RTK activation) and anti-tubulin properties, showing efficacy in preclinical cancer models and is in clinical development.
- High expression of RTKs and tubulins is common in various cancers, indicating potential therapeutic targets.
Purpose of the Study:
- To develop and characterize [11C]AG-488, a radiolabeled tracer with dual inhibitory activity against RTKs and tubulin.
- To evaluate the potential of [11C]AG-488 for cancer imaging by assessing its tumor-to-tissue ratio and blood-brain barrier penetration.
- To investigate the binding characteristics of [11C]AG-488 in vivo using blocking studies.
Main Methods:
- Synthesis of [11C]AG-488 via radiomethylation with a radiochemical yield of 35 ± 5%.
- MicroPET imaging studies in mice to assess blood-brain barrier penetration and brain retention.
- In vivo blocking studies using an RTK inhibitor (HD-800) and a microtubule depolymerizing agent (MPC-6827) to elucidate tracer binding mechanisms.
Main Results:
- [11C]AG-488 demonstrated penetration of the blood-brain barrier and retention in the brain of mice.
- Blocking studies with HD-800 and MPC-6827 resulted in increased binding of [11C]AG-488 in the brain, with a similar binding pattern to baseline conditions.
- The observed increased binding in blocking studies may be attributed to increased plasma uptake of the radiotracer or altered tubulin dynamics.
Conclusions:
- [11C]AG-488 is a novel dual-target inhibitor with potential applications in cancer drug development and imaging.
- The tracer exhibits blood-brain barrier penetration and brain retention, warranting further investigation into its pharmacokinetic and pharmacodynamic properties.
- The precise mechanisms underlying the increased brain binding observed in blocking studies require further elucidation.
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