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. ¹²³I/¹³¹I-MIBG theranostics have been applied in the clinical evaluation and management of neuroendocrine tumors, especially in neuroblastoma, paraganglioma, and pheochromocytoma. ¹²³I-MIBG imaging is a mainstay in the evaluation of neuroblastoma, and ¹³¹I-MIBG has been used for the treatment of relapsed high-risk neuroblastoma for several years, however, the outcome remains suboptimal. ¹³¹I-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.

Keywords: 18F-MFBG; MIBG; neuroblastoma; neuroendocrine; norepinephrine transporter.

FIGURE 1.

Metaiodobenylguanidine (A) and noradrenaline (B).

FIGURE 2.

Imaging with ¹²³I-MIBG and ¹⁸F-MFBG. ¹²³I-MIBG whole-body anterior (A) and posterior (B) images show minimal uptake in bilateral femora (arrows). These lesions are better visualized on ¹⁸F-MFBG PET/CT imaging (C), which also shows additional lesions (blue arrows) not seen on ¹²³I-MIBG imaging.

FIGURE 3.

12-y-old with neuroblastoma. ¹²³I-MIBG pretherapy anterior (A) and posterior (B) images show multiple foci of uptake consistent with lesions in skull, right humerus, vertebrae, pelvic bones, and right tibia (arrows). These lesions are not seen in posttherapy scans (C and D) obtained 8 wk after treatment with 21.8 GBq (590 mCi) of ¹³¹I-MIBG (dose of 666 MBq [18 mCi]/kg).

FIGURE 4.

Patient with metastatic pheochromocytoma presented with progression of disease. ¹²³I-MIBG pretherapy anterior (A) and posterior (B) images show increased uptake in bilateral lung lesions and intense uptake in large sternal lesion, left adrenal lesion, and sacral lesion (arrows). Patient was eligible for ¹³¹I-MIBG and was treated with approximately 8,510 MBq (230 mCi) of ¹³¹I-MIBG. (C–G) Posttherapy planar anterior (C) and posterior (D) scans and SPECT/CT fused images at 3 levels (E–G) show good targeting of lesions (arrows). Plasma normetanephrine and total metanephrine levels decreased from greater than 20,000 and 40,000 pg/mL, respectively, at baseline to 14,295 and 14,329 pg/mL, respectively, at 13 wk after treatment.