The human norepinephrine transporter (hNET) is a transmembrane protein responsible for reuptake of norepinephrine in presynaptic sympathetic nerve terminals and adrenal chromaffin cells. Neural crest tumors, such as neuroblastoma, paraganglioma and pheochromocytoma often show high hNET expression. Molecular imaging of these tumors can be done using radiolabeled norepinephrine analogs that target hNET. Currently, the most commonly used radiopharmaceutical for hNET imaging is meta-[ 123 I]iodobenzylguanidine ([ 123 I]MIBG) and this has been the case since its development several decades ago. The γ-emitter, iodine-123 only allows for planar scintigraphy and SPECT imaging. These modalities typically have a poorer spatial resolution and lower sensitivity than PET. Additional practical disadvantages include the fact that a two-day imaging protocol is required and the need for thyroid blockade. Therefore, several PET alternatives for hNET imaging are actively being explored. This review gives an in-depth overview of the current status and recent developments in clinical trials leading to the next generation of clinical PET ligands for imaging of hNET-expressing tumors.

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