Something old has become new: PET imaging of neural-crest tumors with [18F]-meta-fluorobenzylguanidine

Nuclear medicine and its applications combining diagnosis and therapy in a unique approach, namely “theragnostics or theranostics”, has always played a pivotal role in the work-flow of neural crest-derived tumors (NCTs). Although rare, NCTs represent some important and multifaceted clinical entities, encompassing pheochromocytoma (PHEO), paraganglioma (PGL), and neuroblastoma (NB), this latter being the most frequently diagnosed solid tumor in the 1st year of life [1, 2]. In past years, several molecular probes ([111In]-pentetreotide, [68 Ga]-DOTA-peptides, [18F]-DOPA), have been employed for NCT imaging, some of which also proved useful for intraoperative detection and peptide radionuclide receptor therapy [3, 4]. In this regard, norepinephrine transporter, a transmembrane protein responsible for reuptake of norepinephrine in synaptic nerve, historically represents the “star target” in the field. Iodine123-labeled meta-iodobenzylguanidine ([123I]-mIBG), a synthetic analog of norepinephrine, has been widely employed for NCT detection, staging and follow-up, while its therapeutic counterpart ([131I]-mIBG) has been successfully applied in several clinical trials with good results [5]. However, in spite of its widespread use as an imaging agent, [123I]-mIBG presents well-known relevant drawbacks: first, it requires a multi-day protocol (2 days) and thyroid blockade; second, 123I is a gamma-emitter, therefore allowing detection with gamma-camera, with meaningful limitations in terms of sensitivity and spatial resolution, only partially overcome by the introduction of hybrid single photon tomography/computed tomography (SPECT/CT). In this respect, positron emission computed tomography (PET/CT) technology is characterized by higher sensitivity and specificity, allows the measurement of quantitative parameters and is usually performed in a single-day session. In addition, when carried out through the highly performing silicon-based photomultiplier (SiPM) detectors (the so-called “digital PET/CT”), fast or low-dose protocols can be implemented, thus increasing patients’ comfort, compliance and meaningfully reducing the overall radiation burden, a particularly relevant issue in the case of pediatric population. All the aforementioned considerations strongly triggered researchers to label norepinephrine analog with radionuclides suitable for the imaging with PET/CT. However, first attempts to label mIBG with the positron-emitting iodine-124 ([124I]-mIBG) led to unsatisfying results, due to 124I complex pathway of decay, with the emission of high-energy gamma-rays and unfavorable dosimetry [6]. Consequently, several efforts have been made for obtaining a norepinephrine analog labeled with fluorine-18 (18F), the most commonly employed radionuclide in PET imaging. In this regard, Hu et al. reported a practical, two-step, automated procedure for the synthesis of [18F]-meta-fluorobenzylguanidine ([18F]-mFBG) [7]. Table 1 summarizes the main findings of clinical studies carried out with [18F]-mFBG, as compared to the “old-fashioned” [123I]-mIBG. In a first-in-human PET/CT imaging study in patients bearing NCT lesions positive on [123I]-mIBG scintigraphy, [18F]-mFBG showed physiological activity in liver, lacrimal and salivary gland, left ventricle, adrenals, kidneys and spleen, with a decreasing trend over time, enabling the detection of soft tissue and skeletal lesions with high contrast as early as at 1–2 h after injection (i.e., maximum standardized uptake value/SUVmax resulted in 8.6 at 1–2 h) [8]. The whole-body clearance of * Luca Filippi lucfil@hotmail.com

Nuclear medicine and its applications combining diagnosis and therapy in a unique approach, namely "theragnostics or theranostics", has always played a pivotal role in the work-flow of neural crest-derived tumors (NCTs). Although rare, NCTs represent some important and multifaceted clinical entities, encompassing pheochromocytoma (PHEO), paraganglioma (PGL), and neuroblastoma (NB), this latter being the most frequently diagnosed solid tumor in the 1st year of life [1,2]. In past years, several molecular probes ([ 111 In]-pentetreotide, [ 68 Ga]-DOTA-peptides, [ 18 F]-DOPA), have been employed for NCT imaging, some of which also proved useful for intraoperative detection and peptide radionuclide receptor therapy [3,4]. In this regard, norepinephrine transporter, a transmembrane protein responsible for reuptake of norepinephrine in synaptic nerve, historically represents the "star target" in the field. Iodine-123-labeled meta-iodobenzylguanidine ([ 123 I]-mIBG), a synthetic analog of norepinephrine, has been widely employed for NCT detection, staging and follow-up, while its therapeutic counterpart ([ 131 I]-mIBG) has been successfully applied in several clinical trials with good results [5].
However, in spite of its widespread use as an imaging agent, [ 123 I]-mIBG presents well-known relevant drawbacks: first, it requires a multi-day protocol (2 days) and thyroid blockade; second, 123 I is a gamma-emitter, therefore allowing detection with gamma-camera, with meaningful limitations in terms of sensitivity and spatial resolution, only partially overcome by the introduction of hybrid single photon tomography/computed tomography (SPECT/CT). In this respect, positron emission computed tomography (PET/CT) technology is characterized by higher sensitivity and specificity, allows the measurement of quantitative parameters and is usually performed in a single-day session. In addition, when carried out through the highly performing silicon-based photomultiplier (SiPM) detectors (the so-called "digital PET/CT"), fast or low-dose protocols can be implemented, thus increasing patients' comfort, compliance and meaningfully reducing the overall radiation burden, a particularly relevant issue in the case of pediatric population. All the aforementioned considerations strongly triggered researchers to label norepinephrine analog with radionuclides suitable for the imaging with PET/CT. However, first attempts to label mIBG with the positron-emitting iodine-124 ([ 124 I]-mIBG) led to unsatisfying results, due to 124 I complex pathway of decay, with the emission of high-energy gamma-rays and unfavorable dosimetry [6]. Consequently, several efforts have been made for obtaining a norepinephrine analog labeled with fluorine-18 ( 18 F), the most commonly employed radionuclide in PET imaging. In this regard, Hu et al. reported a practical, two-step, automated procedure for the synthesis of [ 18 F]-meta-fluorobenzylguanidine ([ 18 F]-mFBG) [7]. Table 1 summarizes the main findings of clinical studies carried out with [ 18 F]-mFBG, as compared to the "old-fashioned" [ 123 I]-mIBG. In a first-in-human PET/CT imaging study in patients bearing NCT lesions positive on [ 123 I]-mIBG scintigraphy, [ 18 F]-mFBG showed physiological activity in liver, lacrimal and salivary gland, left ventricle, adrenals, kidneys and spleen, with a decreasing trend over time, enabling the detection of soft tissue and skeletal lesions with high contrast as early as at 1-2 h after injection (i.e., maximum standardized uptake value/SUVmax resulted in 8.6 at 1-2 h) [8]. The whole-body clearance of  [9]. Concerning the biodistribution study, the authors applied a substantially identical protocol with respect to the previously cited paper [8], reporting overlapping results. The pharmacokinetics' analysis in the PHEO subgroup showed a regional distribution volumes (VT) of 37.4 mL/cm 3 . The quality of the image was very high, with an average tumor-to-background ratio and SUVmax in lesions of 23.6 ± 8.4 and 23.6 ± 8.4, respectively, at 1 h after i.v. injection. Notably, the radiocompound administration was safe, with no side effects either in adults or in the child. Concerning the diagnostic performance, all the lesions detected on [ 123 I]-mIBG scintigraphy were also visualized on [ 18 F]-mFBG PET/CT that was able to identify a meaningfully greater number of lesions in all the enrolled patients ([ 123 I]-mIBG detection rate = 61.0% ± 26.7% vs. [ 18 F]-mFBG = 99.8% ± 0.5% at 1 h). In particular, in 1 case a correction was made for lesions that appeared confluent on [ 123 I]-mIBG scan due to the relatively low spatial resolution and were indeed distinctly visualized on [ 18 F]-mFBG PET/CT. Notably, [ 123 I]-mIBG scintigraphy is commonly employed for calculating the SIOPEN prognostic score to determine the extension of the skeletal involvement through a scale ranging 0-6 in 12 anatomical regions [10]: due to its higher detection rate, [ 18 F]-mFBG PET/CT provided a higher SIOPEN score in patients with bone lesions.
In a recently published prospective cross-sectional study, twenty patients affected by NB, submitted to [ 123 I]-mIBG scintigraphy as a part of their standard diagnostic work-up, also underwent [ 18 F]-mFBG PET/CT within an interval of 2 weeks before or after [ 123 I]-mIBG scan [11]. After the administration of [ 18 F]-mFBG (i.e., 2 MBq/Kg), PET/CT was acquired at 1 and 2 h to determine the optimal timepoint for image acquisition. In 2 subjects showing greater compliance to the examination, a 70-min dynamic PET scan was performed, starting with a 6-min scan of the heart region followed by a series of 16 total-body passes, the last two of which were then combined to obtain the 1-h PET/CT image. The authors calculated tracer incorporation in lesions at 1  Although very preliminary, mainly focused on NB and encompassing small cohorts of patients, the initial experiences with [ 18 F]-mFBG are very encouraging. [ 18 F]-mFBG administration was safe, also not requiring patient pre-medication with potassium iodide (KI) or other thyroid blockers. In addition PET/CT imaging resulted associated with a plethora of advantages: higher image contrast, spatial resolution, possibility of a whole body 3D scan and reliability of quantification. Notably, PET/CT acquisition resulted feasible as early as at 1 h after tracer administration, thus avoiding long waiting-times and dual-day protocols, particularly uncomfortable in the case of pediatric population. Indeed, it has been reported that the implementation of [ 18 F]-mFBG PET/CT led to a reduced use of sedative medication in NB patients with respect to [ 123 I]-mIBG, thanks to the shorter duration of the scan (Fig. 1) [11][12][13]. It is worth mentioning that, as reported in the previously cited papers [9,11], [ 18 F]-mFBG PET/CT significantly impacted on the calculation of SIOPEN score, providing a higher value than that calculated on [ 123 I]-mIBG scintigraphy. However, if and how much mFBG-based calculation might impact on the prognostic value of SIOPEN score in clinical practice is still unclear and will be topic of future investigations.
Total effective dose calculated for [ 18 F]-mFBG resulted very favorable, lower than that obtained for [ 123 I]-mIBG, a data of great relevance for radiosensitive pediatric population and when repeated examinations are needed for therapy response assessment. However, although extremely interesting, these preliminary reports should be cautiously interpreted. First of all, dosimetry calculation has been performed in a very limited number of subjects, thus it requires further confirmation. In this regard, it has still to be investigated the possible contribution of hybrid PET/ MRI not only to further reduce ionizing radiation dose eliminating the CT-component but also for a better depiction of lesions thanks to MRI superior image contrast [14]. Furthermore, the diagnostic performance of [ 18 F]-mFBG with respect to the already mentioned tracers commonly employed for NCT imaging, other than [ 123 I]-mIBG, has still to be addressed [15]. In this regard, Wang  F]-mFBG has not been approved by the regulatory authorities (Food and Drug Administration, European Medicines Agency) yet, it is not commercially available and can be used only within clinical trials. In the next future, tracer supplementation and benefit/cost analysis, still to be determined, will be game-changers, since they might heavily impact on [ 18 F]-mFBG potential implementation in clinical practice. In spite of these still unsolved issues, the new era of [ 18 F]-mFBG PET/CT seems next to come, holding the promise to move forward the field of NCT imaging.
Author contributions All the authors equally contributed to conception and design of the article, or acquisition, analysis and interpretation of data.
Funding No funding was received.
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Declarations
Conflict of interest L.F. and O.S. declare that they have no competing interest.
Ethical approval and consent to participate Not applicable.
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