Radiopharmacologist’s and Radiochemist’s View on Targeting the Eph/Ephrin Receptor Tyrosine Kinase System

Abstract

In the past decade, there have been extensive efforts to open up the Eph/ephrin subfamily of the receptor tyrosine kinase family for diagnostic and therapeutic applications. Besides classical pharmaceutical developments, which focus either on drugs targeting the extracellular ligand binding domains or on the intracellular tyrosine kinase domains of these receptors, there also have been first radiopharmaceutical approaches. Here the focus is on the development of specific and selective probes for molecular imaging, particularly by means of positron emission tomography, and the functional characterization of the Eph/ephrin subfamily in certain target tissues. The aim of this mini-review is to summarize the different approaches toward Eph-targeting radiotracers by using antibodies, peptides, and small molecules and to discuss their radiopharmacological characterization. With regard to the small molecules, further considerations will focus on the design and synthesis of nonradioactive reference compounds and precursors as well as on radiolabeling strategies.

Strained Ammonium Precursors for Radiofluorinations

“…[82] Instead, [ 18 F]AFP was used for the radiolabelling of the SNEW peptide [ 18 F]62, [83] which is known to be a substrate for the EphB4 receptor, and for radiolabelling the SWLAY peptide [ 18 F]61, [84] (Scheme 18) which is known to be a substrate for the EphA2 receptor. [85] A high-affinity EphB4 receptor ligand (box in Scheme 19) published by Bardelle et al [86] was used as basis for the development of potential PET radiotracers with fluorine-18 and carbon-11. [87,88] The position for the introduction of carbon-11 was easy to find because of the prominent methyl group in the molecule, allowing for the use of [ 11 C]methyl iodide for radiolabelling.…”

Protein-Protein Interaction Inhibitors Targeting the Eph-Ephrin System with a Focus on Amino Acid Conjugates of Bile Acids

“…Advances in this field have been recently discussed in the literature [70]. These inhibitors were further exploited as biological tools for the development of radiotracers, to investigate the role and impact of the Eph-ephrin system in cancer, as recently described by Neuber et al [71].…”

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

“…Different approaches towards Eph-targeting radiopharmaceuticals were recently reviewed [ 351 ]. Eph receptors are often expressed on migrating tumor cells, especially at the edge where GB cells are actively invading into the brain parenchyma.…”

“…The main challenge remains the high conservation of the ATP-binding pocket, resulting in a usually low selectivity of such compounds. However, this could be advantageous in case of TRT to target multiple pathways concomitantly [ 351 ].…”

“…In contrast, a peptide-based radiopharmaceutical [ 64 Cu]Cu-TNYL-RAW, was useful for PET/CT imaging of EphB4 receptor expression, with specific uptake in both U251 and U87MG GB tumor bearing mice [ 357 , 360 ]. Other EphR targeting peptides, including SWL and SNEW, have been radiolabeled ( Table S1 ) [ 351 , 361 ]. Finally, the recently developed [ 18 F]-labeled xanthine derivatives have potential for PET imaging of Eph receptors but lack studies in GB to date [ 362 ].…”