Norepinephrine Transporter as a Target for Imaging and Therapy

Abstract

The norepinephrine transporter (NET) is essential for norepinephrine uptake at the synaptic terminals and adrenal chromaffin cells. In neuroendocrine tumors, NET can be targeted for imaging as well as therapy. One of the most widely used theranostic agents targeting NET is metaiodobenzylguanidine (MIBG), a guanethidine analog of norepinephrine. 123 I/ 131 I-MIBG theranostics have been applied in the clinical evaluation and management of neuroendocrine tumors, especially in neuroblastoma, paraganglioma, and pheochromocytoma. 123 I-MIBG imaging is a mainstay in the evaluation of neuroblastoma, and 131 I-MIBG has been used for the treatment of relapsed high-risk neuroblastoma for several years, however, the outcome remains suboptimal. 131 I-MIBG has essentially been only palliative in paraganglioma/pheochromocytoma patients. Various techniques of improving therapeutic outcomes, such as dosimetric estimations, high-dose therapies, multiple fractionated administration and combination therapy with radiation sensitizers, chemotherapy, and other radionuclide therapies, are being evaluated. PET tracers targeting NET appear promising and may be more convenient options for the imaging and assessment after treatment. Here, we present an overview of NET as a target for theranostics; review its current role in some neuroendocrine tumors, such as neuroblastoma, paraganglioma/ pheochromocytoma, and carcinoids; and discuss approaches to improving targeting and theranostic outcomes.

Syntheses and evaluation of 68Ga‐ and 153Sm‐labeled DOTA‐conjugated bisphosphonate ligand for potential use in detection of skeletal metastases and management of pain arising from skeletal metastases

“…[8][9][10][11] Among these, 153 Sm-complex of polyaminophosphonate ligand EDTMP (ethylenediaminetetramethylene phosphonic acid) has been used most extensively over the past three decades. [12,13] Introduction of 68 Ge/ 68 Ga generator system and 68 Garadiopharmaceuticals in nuclear medicine brought a paradigm shift in the detection of skeletal metastases in patients with cancer by PET imaging where detection of very small metastatic lesions, which otherwise not detected in conventional 99m Tc-MDP scintigraphy, became possible. Studies have established that 68 Ga-complexes of polyaminophosphonate ligands, such as EDTMP, where phosphonate group is coordinated to Ga 3+ demonstrate suboptimal skeletal accumulation.…”

A “mix‐and‐use” approach for formulation of human clinical doses of 177Lu‐DOTMP at hospital radiopharmacy for management of pain arising from skeletal metastases

“…The developed "mix-and-use" strategy would be useful for large number of nuclear medicine centers having access to 177 Radionuclide therapy by systemic administration of suitable bone-seeking therapeutic radiopharmaceuticals has evolved as one of the most efficient and appealing modality for palliation of pain in patients with multifocal skeletal metastases arising out of primary carcinoma in the breast, lung, prostate, etc. [1][2][3][4] Despite a growing number of radionuclides and a host of various radiolabeled formulations investigated for palliative care of skeletal metastases, 153 Sm-EDTMP (Quadramet) (EDTMP = ethylenediaminetetramethylene phosphonic acid) is still the most extensively used radiopharmaceutical in clinical context. [5][6][7] This is mainly attributed to the fact that Quadramet shows excellent human pharmacokinetic properties and efficacy in alleviating pain with myelotoxicity and other side effects within acceptable limits.…”

“…[1][2][3][4] Despite a growing number of radionuclides and a host of various radiolabeled formulations investigated for palliative care of skeletal metastases, 153 Sm-EDTMP (Quadramet) (EDTMP = ethylenediaminetetramethylene phosphonic acid) is still the most extensively used radiopharmaceutical in clinical context. [5][6][7] This is mainly attributed to the fact that Quadramet shows excellent human pharmacokinetic properties and efficacy in alleviating pain with myelotoxicity and other side effects within acceptable limits. 5,6,[8][9][10] However, there are some practical issues associated with formulation and use of this radiopharmaceutical.…”

“…[5][6][7] This is mainly attributed to the fact that Quadramet shows excellent human pharmacokinetic properties and efficacy in alleviating pain with myelotoxicity and other side effects within acceptable limits. 5,6,[8][9][10] However, there are some practical issues associated with formulation and use of this radiopharmaceutical. The main disadvantage is the relatively short half-life (T ½ = 1.93 d) of 153 Sm.…”

Theranostic Concepts: More Than Just a Fashion Trend—Introduction and Overview

“…Use of the norepinephrine transporter as a theranostic target is presented by Pandit-Taskar and Modak (13). In addition to the numerous peptide ligands and small molecules, several theranostic antibodies have also been developed; Moek et al summarize these (14).…”