Navigating new horizons: Prospects of NET-targeted radiopharmaceuticals in precision medicine

Abstract

In the evolving landscape of precision medicine, NET-targeted radiopharmaceuticals are emerging as pivotal tools for the diagnosis and treatment of a range of conditions, from heart failure and neurodegenerative disorders to neuroendocrine cancers. This review evaluates the advancements offered by ¹⁸F-labeled PET tracers and ²¹¹At alpha-particle therapy, juxtaposed with current ¹²³I-MIBG SPECT and ¹³¹I-MIBG therapies. The enhanced spatial resolution and capability for quantitative analysis render ¹⁸F-labeled PET tracers potential candidates for improved detection and management of diseases. Alpha-particle therapy with ²¹¹At may offer increased specificity and tumoricidal efficacy, pointing towards a shift in therapeutic protocols. While preliminary data is promising, these innovative approaches require thorough validation against current modalities. Ongoing clinical trials are pivotal to confirm the expected clinical benefits and to address safety concerns. This review underscores the need for rigorous research to verify the clinical utility of NET-targeted radiopharmaceuticals, which may redefine precision medicine paradigms and significantly impact patient care.

Keywords: Alpha-particle; Astatine; MIBG; Norepinephrine; PET; neuroendocrine tumor.

Figure 1

Illustration of the dynamics of norepinephrine and analogous radioactive tracers at cardiac sympathetic nerve endings. It depicts how Parkinson's disease and heart failure affect cardiac tracer uptake. In Parkinson's disease, the accumulation of alpha-synuclein at the terminals of cardiac sympathetic nerves leads to their denervation, resulting in reduced tracer uptake by the heart. Conversely, in heart failure, there is an upregulation of sympathetic nervous activity, which elevates norepinephrine levels in the synaptic cleft, thereby inhibiting tracer uptake due to competitive mechanisms. Created with BioRender.com.

Figure 2

¹⁸F-AF78 demonstrated high NET affinity and advantageous in vivo radiotracer kinetics across various species. (A) A protocol for the one-pot, two-step radiolabeling of NET-targeting tracer ¹⁸F-AF78. (B) In vivo studies of radiotracer distribution in healthy rats confirm that ¹⁸F-AF78(F) showing highest contrast cardiac uptake among meta-substituents on the benzene ring. (C) PET scans reveal clear imaging of cardiac tissue (left) and brown adipose tissue uptake (right) in healthy rats using ¹⁸F-AF78(F). (D) Comparative PET scans of non-human primates (NHPs), with and without the NET-selective inhibitor desipramine, demonstrate the specificity of ¹⁸F-AF78 in cardiac imaging. Adapted with permission from , Copyright 2023, MDPI.

Figure 3

Planar scintigraphy with ¹²³I-MIBG (A) and the corresponding fused SPECT/CT (B), along with ¹⁸F-MFBG PET maximum intensity projection (MIP) (C) and fused PET/CT (D), were conducted on a patient with neuroblastoma. Short arrows in images (A and C) illustrate normal physiological uptake in the salivary glands and the renal pelvicalyceal system. Areas of additional uptake represent tumor lesions. Long red arrows identify extra mediastinal lymph node metastases that are captured by ¹⁸F-MFBG PET, showcasing its superior sensitivity, but these were not on ¹²³I-MIBG scans. Adapted with permission from Copyright 2022, Springer Nature.

Figure 4

Evolutionary phylogeny of Norepinephrine Transporter (NET) radiotracers. This phylogenetic tree traces the development of selected NET-targeting radiotracers, classified into two main categories: monoamines (indicated by the violet cloud) and guanidines (denoted by the light green cloud). Shared molecular frameworks within the radiotracers are color-coded to illustrate structural similarities—core structures in blue and green, and the ubiquitous "tail" motif in orange. The placement of radionuclides within the molecular structures is highlighted in red. Adapted with permission from , Copyright 2023, MDPI.

Figure 5

Alpha-particles, like ²¹¹At, offer the potential to combine cell-specific molecular targets with radiation that has a range in tissue of only a few cells (0.06 mm), which is different to beta-particles, such as ¹³¹I, that have a maximum range of around 0.8 mm. The distinct advantages of alpha particles, such as their potent cytotoxicity and selective targeting, position targeted alpha therapy as a promising avenue in the field of cancer treatment. Created with BioRender.com.

Figure 6

The ²¹¹At-MABG-treated mice showed significantly lower relative tumor growth in mice with PC12 pheochromocytoma cells: a) Tumor growth trajectories following ²¹¹At-MABG administration demonstrate significant reduction. b) Day 21 post-treatment images of mice, comparing ²¹¹At-MABG treatment, with tumors highlighted by dashed circles. Adapted with permission from . Copyright 2018, Springer Nature.

Figure 7

Advancements in Radiopharmaceuticals for NET Targeting: This illustration summarizes the progress in diagnostic and therapeutic agents, highlighting the integration of PET for high-resolution, sensitive imaging, and the employment of alpha-emitting nuclides for focused radiation therapy. These innovations herald a new era of precision medicine with enhanced diagnostic and treatment capabilities. Created with BioRender.com.