Development of a Radiolabeled Cyclin-Dependent Kinases 4 and 6 (CDK4/6) Inhibitor for Brain and Cancer PET Imaging

Area of Science:

• Oncology
• Radiochemistry
• Pharmacology

Background:

• Cyclin-dependent kinases 4 and 6 (CDK4/6) are crucial targets in cancer therapy.
• Abemaciclib is an FDA-approved CDK4/6 inhibitor, but its efficacy in brain metastases is limited by blood-brain barrier (BBB) penetration.
• Developing novel CDK4/6 inhibitors with enhanced BBB penetration is essential for treating central nervous system (CNS) malignancies.

Purpose of the Study:

• To synthesize and evaluate NT431, a novel 4-fluorobenzyl-abemaciclib derivative, as a CDK4/6 inhibitor and radioligand.
• To assess the potential of [18F]NT431 for imaging CDK4/6-positive tumors, including those in the brain.
• To determine the BBB penetration and brain uptake of [18F]NT431 and its parent compound, abemaciclib.

Main Methods:

• Synthesis and biochemical evaluation of NT431 for CDK4/6 inhibition.
• Two-step one-pot radiosynthesis of [18F]NT431.
• In vitro autoradiography using brain tissues.
• Dynamic positron emission tomography (PET) imaging in vivo.

Main Results:

• NT431 demonstrated high potency against CDK4/6 and cancer cell lines, comparable to abemaciclib.
• [18F]NT431 was produced with good radiochemical yield, high purity, and high molar activity.
• In vitro and in vivo studies confirmed specific binding to CDK4/6 and BBB penetration, but with modest brain uptake for both [18F]NT431 and abemaciclib.
• Neither compound is expected to accumulate sufficiently in the brain for effective treatment of brain metastases or primary brain cancers.

Conclusions:

• NT431 is a potent CDK4/6 inhibitor with potential for peripheral tumors.
• [18F]NT431 shows promise for visualizing CDK4/6-positive peripheral tumors.
• The modest BBB penetration of NT431 and abemaciclib limits their utility for CNS applications.
• Further development of CDK4/6 inhibitors with superior BBB penetration is needed for CNS tumor treatment and imaging.