Recent Advances in the Development and Application of Radiolabeled Kinase Inhibitors for PET Imaging

Abstract

Abstract:Over the last 20 years, intensive investigation and multiple clinical successes targeting protein kinases, mostly for cancer treatment, have identified small molecule kinase inhibitors as a prominent therapeutic class. In the course of those investigations, radiolabeled kinase inhibitors for positron emission tomography (PET) imaging have been synthesized and evaluated as diagnostic imaging probes for cancer characterization. Given that inhibitor coverage of the kinome is continuously expanding, in vivo PET imaging will likely find increasing applications for therapy monitoring and receptor density studies both in-and outside of oncological conditions. Early investigated radiolabeled inhibitors, which are mostly based on clinically approved tyrosine kinase inhibitor (TKI) isotopologues, have now entered clinical trials. Novel radioligands for cancer and PET neuroimaging originating from novel but relevant target kinases are currently being explored in preclinical studies. This article reviews the literature involving radiotracer design, radiochemistry approaches, biological tracer evaluation and nuclear imaging results of radiolabeled kinase inhibitors for PET reported between 2010 and mid-2015. Aspects regarding the usefulness of pursuing selective vs. promiscuous inhibitor scaffolds and the inherent challenges associated with intracellular enzyme imaging will be discussed.

Effect of co-administration of Bee honey and some chemotherapeutic drugs on dissemination of hepatocellular carcinoma in rats

“…Recently, tyrosine kinase inhibitors had been approved as clinical strategy to treat cancer [24]. Honey and honey products were found to be effective as suppressors of tyrosine kinase activity and induction of cell cycle arrest in G1 or G2/M phase [25], and selective inhibition of cancerous cell viability [26,27].…”

One‐step synthesis of [18F]cabozantinib for use in positron emission tomography imaging of c‐Met

“…By using PET, the target expression for a certain drug can be assessed in vivo, and this could give vital clinical information resulting in a more targeted and effective treatment. Several of the FDA‐approved kinase inhibitors have in recent years been labelled with positron emitting nuclides and investigated as PET tracers . Overexpression of c‐Met in several tumors motivates the use of PET, and studies have been performed with a small‐molecule, a monoclonal antibody, and hepatocyte growth factor itself .…”

Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib

“…Unfortunately, imaging receptor tyrosine kinases and their associated signal transduction pathways with isotopologues of potent and selective drugs are rarely explored for oncology and neuroimaging 22 23 24 25 26 27 with positron emission tomography (PET). This lack of effort is partially attributed to the additional challenges of imaging intracellular targets, compared to high-density receptor and enzyme targets at the extracellular domain, and competition at binding sites with high intracellular levels of ATP.…”