Imaging Of Neuroendocrine Tumors Research Articles

Imaging of pancreatic neuroendocrine tumors

Neuroendocrine tumors of the pancreas have abroad biological spectrum. The treatment decision is based on an optimal diagnosis with regard to the local findings and possible locoregional and distant metastases. In addition to purely morphologic imaging procedures, functional parameters are playing an increasingly important role in imaging. Prerequisites for optimal imaging of the pancreas, technical principles are provided, and the advantages and disadvantages of common cross-sectional imaging techniques as well as clinical indications for these special imaging methods are discussed. Guidelines, basic and review papers will be analyzed. Neuroendocrine tumors of the pancreas have abroad imaging spectrum. Therefore, there is aneed for multimodality imaging in which morphologic and functional techniques support each other. While positron emission tomography/computed tomography (PET/CT) can determine the presence of one or more lesions and its/their functional status of the tumor, magnetic resonance imaging (MRI) efficiently identifies the location, relationship to the main duct and the presence of liver metastases. CT allows abetter vascular evaluation, even in the presence of anatomical variants as well as sensitive detection of lung metastases. Knowledge of the optimal combination of imaging modalities including clinical and histopathologic results and dedicated imaging techniques is essential to achieve an accurate diagnosis to optimize treatment decision-making and to assess therapy response.

Validation of the standardization framework SSTR-RADS 1.0 for neuroendocrine tumors using the novel SSTR‑targeting peptide [18F]SiTATE.

Somatostatin receptor positron emission tomography/computed tomography (SSTR-PET/CT) using [68Ga]-labeled tracers is a widely used imaging modality for neuroendocrine tumors (NET). Recently, [18F]SiTATE, a SiFAlin tagged [Tyr3]-octreotate (TATE) PET tracer, has shown great potential due to favorable clinical characteristics. We aimed to evaluate the reproducibility of Somatostatin Receptor-Reporting and Data System 1.0 (SSTR-RADS 1.0) for structured interpretation and treatment planning of NET using [18F]SiTATE. Four readers assessed [18F]SiTATE-PET/CT of 95 patients according to the SSTR-RADS 1.0 criteria at two different time points. Each reader evaluated up to five target lesions per scan. The overall scan score and the decision on peptide receptor radionuclide therapy (PRRT) were considered. Inter- and intra-reader agreement was determined using the intraclass correlation coefficient (ICC). The ICC analysis on the inter-reader agreement using SSTR-RADS 1.0 for identical target lesions (ICC ≥ 85%), overall scan score (ICC ≥ 90%), and the decision to recommend PRRT (ICC ≥ 85%) showed excellent agreement. However, significant differences were observed in recommending PRRT among experienced readers (ER) (p = 0.020) and inexperienced readers (IR) (p = 0.004). Compartment-based analysis demonstrated good to excellent inter-reader agreement for most organs (ICC ≥ 74%), except for lymph nodes (ICC ≥ 53%). SSTR-RADS 1.0 represents a highly reproducible and consistent framework system for stratifying SSTR-targeted PET/CT scans, even using the novel SSTR-ligand [18F]SiTATE. Some inter-reader variability was observed regarding the evaluation of uptake intensity prior to PRRT as well as compartment scoring of lymph nodes, indicating that those categories require special attention during further clinical validation and might be refined in a future SSTR-RADS version 1.1. SSTR-RADS 1.0 is a consistent framework for categorizing somatostatin receptor-targeted PET/CT scans when using [18F]SiTATE. The framework serves as a valuable tool for facilitating and improving the management of patients with NET. SSTR-RADS 1.0 is a valuable tool for managing patients with NET. SSTR-RADS 1.0 categorizes patients with showing strong agreement across diverse reader expertise. As an alternative to [68Ga]-labeled PET/CT in neuroendocrine tumor imaging, SSTR-RADS 1.0 reliably classifies [18F]SiTATE-PET/CT.

Imaging of Neuroendocrine Neoplasms; Principles of Treatment Strategies. What Referring Clinicians Want to Know

Abstract Neuroendocrine neoplasms (NENs) are a diverse group of tumors that express neuroendocrine markers and primarily affect the lungs and digestive system. The incidence of NENs has increased over time due to advancements in imaging and diagnostic techniques. Effective management of NENs requires a multidisciplinary approach, considering factors such as tumor location, grade, stage, symptoms, and imaging findings. Treatment strategies vary depending on the specific subtype of NEN. In this review, we will focus on treatment strategies and therapies including the information relevant to clinicians in order to undertake optimal management and treatment decisions, the implications of different therapies on imaging, and how to ascertain their possible complications and treatment effects.

Functional imaging in neuroendocrine tumors: assessment of molecular heterogeneity using [68Ga]Ga-DOTA-TOC and [18F]FDG PET/CT

ObjectiveThe aim of the study was evaluate the diagnostic performance of [68Ga]Ga-DOTA-TOC and [18F]FDG PET/CT in patients with histologically proven neuroendocrine tumors (NETs), as well as the correlation of the visualized findings with the tumor grade. Material and methodsWe included 50 patients with NETs who underwent both [68Ga]Ga-DOTA-TOC and [18F]FDG PET/TC. The pooled sensitivity of both scans was compared, as well as [68Ga]Ga-DOTA-TOC and [18F]FDG for each tumor grade (grade 1/G1, grade 2/G2 and grade 3/G3). Also, the sensitivity of [68Ga]Ga-DOTA-TOC and [18F]FDG as a function of the continuous variable Ki-67 was investigated. Finally, the number of lesions detected by both PET radiopharmaceuticals for each tumor grade was compared. ResultsThe pooled sensitivity of both PET/CT (96%) was higher than [68Ga]Ga-DOTA-TOC (84%) and [18F]FDG (44%) separately, with statistically significant differences. The sensitivity of [68Ga]Ga-DOTA-TOC was higher than [18F]FDG in both G1 (p = 0.004) and G2 (p < 0.001). In G3 the performance of both scans detected disease in 100% of this subgroup. The sensitivity of [68Ga]Ga-DOTA-TOC and [18F]FDG PET/CT correlated significantly with the Ki-67 proliferative index. In G2 patients the number of lesions detected with [68Ga]Ga-DOTA-TOC was higher than [18F]FDG. ConclusionsThe performance of both PET/CT, particularly in G2 and G3, demonstrates the molecular heterogeneity of metastatic NETs and contributes to the selection of a more appropriate treatment, particularly in those high-grade patients who may benefit from radionuclide therapy (PRRT).

Somatostatin Receptor Imaging with [18F]FET-βAG-TOCA PET/CT and [68Ga]Ga-DOTA-Peptide PET/CT in Patients with Neuroendocrine Tumors: A Prospective, Phase 2 Comparative Study.

There is a clinical need for 18F-labeled somatostatin analogs for the imaging of neuroendocrine tumors (NET), given the limitations of using [68Ga]Ga-DOTA-peptides, particularly with regard to widespread accessibility. We have shown that [18F]fluoroethyl-triazole-[Tyr3]-octreotate ([18F]FET-βAG-TOCA) has favorable dosimetry and biodistribution. As a step toward clinical implementation, we conducted a prospective, noninferiority study of [18F]FET-βAG-TOCA PET/CT compared with [68Ga]Ga-DOTA- peptide PET/CT in patients with NET. Methods: Forty-five patients with histologically confirmed NET, grades 1 and 2, underwent PET/CT imaging with both [18F]FET-βAG-TOCA and [68Ga]Ga-peptide performed within a 6-mo window (median, 77 d; range, 6-180 d). Whole-body PET/CT was conducted 50 min after injection of 165 MBq of [18F]FET-βAG-TOCA. Tracer uptake was evaluated by comparing SUVmax and tumor-to-background ratios at both lesion and regional levels by 2 unblinded, experienced readers. A randomized, blinded reading of both scans was also then undertaken by 3 experienced readers, and consensus was assessed at a regional level. The ability of both tracers to visualize liver metastases was also assessed. Results: A total of 285 lesions were detected on both imaging modalities. An additional 13 tumor deposits were seen in 8 patients on [18F]FET-βAG-TOCA PET/CT, and [68Ga]Ga-DOTA-peptide PET/CT detected an additional 7 lesions in 5 patients. Excellent correlation in SUVmax was observed between both tracers (r = 0.91; P < 0.001). No difference was observed between median SUVmax across regions, except in the liver, where the median tumor-to-background ratio of [18F]FET-βAG-TOCA was significantly lower than that of [68Ga]Ga-DOTA-peptide (2.5 ± 1.9 vs. 3.5 ± 2.3; P < 0.001). Conclusion: [18F]FET-βAG-TOCA was not inferior to [68Ga]Ga-DOTA-peptide in visualizing NET and may be considered in routine clinical practice given the longer half-life and availability of the cyclotron-produced fluorine radioisotope.

The influence of Q.Clear reconstruction on the contrast recovery coefficient and semi-quantitative parameters of NEMA phantom imaging

Background: The aim of the study is to optimise the value of B parameter (β), which is used in the Q.Clear reconstruction in the imaging of neuroendocrine tumours. The study is divided into two parts: analysis of phantom data aiming at selection of the appropriate β for small changes, and then assessment of its impact on the quality of patients' images. The literature data on the optimal β value are inconclusive. Furthermore, the suggested values are not the result of the semi-quantitative assessment of Standard Uptake Volume (SUV) or the proper verification based on, for example, phantom studies using the known activity. Results: The obtained results show that β increase raises the image uniformity in the Q.Clear reconstruction algorithm. Also, referring to the scientific reports, one can see that the signal to noise ratio in the image increases. The effect of the β change on the SUV mean and Contrast Recovery Coefficient (CRC) value is greatest for the smallest objects. The decrease of this parameter is also much higher with lower values of activity (a lower counts statistic in the PET system). Conclusions: An increase of β has an adverse effect on the quality of a semi-quantitative assessment of SUV – as the parameter increases, the SUV and CRC values decrease. In the visual assessment, a satisfactory image quality is present with β = 450. Based on the analysis of SUV and CRC, an appropriate range of β values was selected as 350–450. At the selected range, a retrospective analysis of the clinical images of neuroendocrine tumours will be performed in the future and the impact of the change on the semi- -quantitative analysis of pathological changes will be verified.

18F-labeled somatostatin analogs for somatostatin receptors (SSTRs) targeted PET imaging of neuroendocrine tumors (NETs)

A novel 18F-radiolabeled somatostatin analogue, [Al18F]NODA-MPAA-HTA, was synthesized and evaluated for positron emission tomography (PET) imaging of Neuroendocrine tumors (NETs). [Al18F]NODA-MPAA-HTA was designed and synthesized by conjugating 18F nuclide with a modified KE108 peptide, a somatostatin analog with high affinity for all five subtypes of somatostatin receptors (SSTR 1-5), through coupling a bifunctional chelator (NODA) to target somatostatin receptor (SSTR) positive tumors. The amino group of KE108 peptide, a SSTRs-targeting pharmacophore, was conjugated with the carboxyl group of NODA by a condensation reaction to obtain the labeling precursor of [Al18F]NODA-MPAA-HTA, in which its precursor was obtained through Fmoc solid-phase methods. A novel methodology for Al18F labeling of chelating agent-biomolecule conjugates was used to synthesize [Al18F]NODA-MPAA-HTA. In vitro stabilities of [Al18F]NODA-MPAA-HTA were evaluated by incubating it in saline or bovine serum for 2h. Ex vivo biodistribution and in vivo imaging of [Al18F]NODA-MPAA-HTA were further investigated to evaluate its SSTRs targeting ability and feasibility for the diagnosis of NETs using PET imaging. [Al18F]NODA-MPAA-HTA was synthesized using a one-step 18F-AlF labeling procedure resulting in moderate radiochemical yield (60-80%, non-decay corrected) and high radiochemical purity (>95%). It exhibited good hydrophilicity and excellent stability in vitro, with a molar activity of 122 GBq/μmol. At 30min and 60min, the uptake of [Al18F] NODA-MPAA-HTA by HEK293-SSTR2 cells was 5.47±0.97%/105 cells and 12.11±0.32%/105 cells, respectively. The affinity of [Al18F]NODA-MPAA-HTA for SSTR2 was determined to be 8.77±1.14nM. In micro-PET imaging of HEK293-SSTR2 tumor-bearing mice, [Al18F]NODA-MPAA-HTA showed high tumor uptake of radioactivity and a high tumor-to-muscle ratio. Biodistribution results confirmed that radioactivity uptake in the tumor was significantly higher than that in the muscle by more than five-fold (P<0.001). Furthermore, the relatively low bone uptake of [Al18F]NODA-MPAA-HTA suggested that defluorination did not occur in vivo. These preliminary results provide experimental evidence for further study of Al18F-labeled somatostatin analogues as tumor probes for PET imaging of NETs. Fluorine-18 is widely used as a radionuclide for the production of radiopharmaceuticals for positron emission tomography (PET). Due to its short half-life (T1/2,109.8min), its ease of production will facilitate the widespread dissemination of this radiopharmaceutical. A high-quality [Al18F]NODA-MPAA-HTA was synthesized with satisfactory yield. This radiopharmaceutical demonstrated higher tumor uptake and better tumor-to-muscle contrast, resulting to excellent image quality. These findings suggest that the novel 18F-labeled somatostatin analogue, [Al18F]NODA-MPAA-HTA, is a promising tool for PET imaging of NETs.

68Ga] DOTA-TATE (NETSpot) PET/CT Imaging of Pulmonary Neuroendocrine Tumors

68Ga] DOTA-TATE (NETSpot) PET/CT Imaging of Pulmonary Neuroendocrine Tumors

Use and perceived utility of [18 F]FDG PET/CT in neuroendocrine neoplasms: A consensus report from the European Neuroendocrine Tumor Society (ENETS) Advisory Board Meeting 2022.

Somatostatin receptor (SST) PET/CT is the gold standard for well-differentiated neuroendocrine tumours (NET) imaging. Higher grades of neuroendocrine neoplasms (NEN) show preferential [18F]FDG (FDG) uptake, and even low-grade NET may de-differentiate over time. FDG PET/CT's prognostic role is widely accepted; however, its impact on clinical decision-making remains controversial and its use varies widely. A questionnaire-based survey on FDG PET/CT use and perceived decision-making utility in NEN was submitted to the ENETS Advisory Board Meeting attendees (November 2022, response rate = 70%). In 3/15 statements, agreement was higher than 75%: (i) FDG was considered useful in NET, irrespective of grade, in case of mis-matched lesions (detectable on diagnostic CT but negative/faintly positive on SST PET/CT), especially if PRRT is contemplated (80%); (ii) in NET G3 if curative surgery is considered (82%); and (iii) in NEC prior to surgery with curative intent (98%). FDG use in NET G3, even in the presence of matched lesions, as a baseline for response assessment was favoured by 74%. Four statements obtained more than 60% consensus: (i) FDG use in NET G3 if locoregional therapy is considered (65%); (ii) in neuroendocrine carcinoma before initiating active therapy as a baseline for response assessment (61%); (iii) biopsy to re-assess tumour grade prior to a change in therapeutic management (68%) upon detection of FDG-positivity on the background of a prior G1-2 NET; (iv) 67% were in favour to reconsider PRRT to treat residual SST-positive lesions after achieving complete remission on FDG of the SST-negative disease component. Multidisciplinary opinion broadly supports the use of FDG PET/CT for characterisation of disease biology and to guide treatment selection across a range of indications, despite the lack of full consensus in many situations. This may reflect existing clinical access due to lack of reimbursement or experience with this investigation, which should be addressed by further research.

Theranostic Nuclear Medicine with Gallium-68, Lutetium-177, Copper-64/67, Actinium-225, and Lead-212/203 Radionuclides.

Molecular changes in malignant tissue can lead to an increase in the expression levels of various proteins or receptors that can be used to target the disease. In oncology, diagnostic imaging and radiotherapy of tumors is possible by attaching an appropriate radionuclide to molecules that selectively bind to these target proteins. The term "theranostics" describes the use of a diagnostic tool to predict the efficacy of a therapeutic option. Molecules radiolabeled with γ-emitting or β+-emitting radionuclides can be used for diagnostic imaging using single photon emission computed tomography or positron emission tomography. Radionuclide therapy of disease sites is possible with either α-, β-, or Auger-emitting radionuclides that induce irreversible damage to DNA. This Focus Review centers on the chemistry of theranostic approaches using metal radionuclides for imaging and therapy. The use of tracers that contain β+-emitting gallium-68 and β-emitting lutetium-177 will be discussed in the context of agents in clinical use for the diagnostic imaging and therapy of neuroendocrine tumors and prostate cancer. A particular emphasis is then placed on the chemistry involved in the development of theranostic approaches that use copper-64 for imaging and copper-67 for therapy with functionalized sarcophagine cage amine ligands. Targeted therapy with radionuclides that emit α particles has potential to be of particular use in late-stage disease where there are limited options, and the role of actinium-225 and lead-212 in this area is also discussed. Finally, we highlight the challenges that impede further adoption of radiotheranostic concepts while highlighting exciting opportunities and prospects.

Effects of somatostatin analogs on uptake of radiolabeled somatostatin analogs on imaging: a systematic review and meta-analysis.

The imaging of somatostatin receptors (SSTRs) plays a significant role in imaging neuroendocrine tumors (NETs). However, there has been no clear definition on whether it is necessary to withdraw somatostatin analogs (SSAs) before SSTRs imaging. We aimed to assess whether nonradioactive SSAs affect the uptake of radiolabeled SSAs on imaging for NETs patients. The databases of PubMed, Embase, and Web of Science (WoS) were searched until March 12, 2022 to identify eligible studies. Maximum standardized uptake values (SUVmax) in tumor and normal tissues were extracted, pooled, and compared before and after SSAs treatment. The change of tumor-to-background/liver ratio was also described. The quality of each study was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies-2 tool. A total of 9 articles involving 285 patients were included and 5 studies using Gallium-68-labeled [1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid]-D-Phe1-Tyr3-Thr8-octreotide (68Ga-DOTATATE) were used for pooled evaluation. We found a significantly decreased SUVmax in the liver (9.56±2.47 vs. 7.62±2.12, P=0.001) and spleen (25.74±7.14 vs. 20.39±6.07, P=0.006) after SSAs treatment whereas no significant differences were observed in the uptake of thyroid, adrenal, and pituitary gland. For either primary tumor sites or metastases, the SUVmax did not change significantly before and after SSAs treatment. The tumor-to-liver/background ratio increased following SSAs therapy. High heterogeneity was observed across the studies, mainly due to inherent diversity of study design, sample size, and scanning technique. Based on current evidence, long-acting SSAs therapy before imaging has no effect on the uptake of radiolabeled SSAs at tumor primary sites and metastatic lesions, but results in a significant reduction of uptake in the liver and spleen. These findings may implicate the unnecessary discontinuation of SSAs before radiolabeled SSAs imaging.

Clinical validation and diagnostic accuracy of 99mTc-EDDA/HYNIC-TOC compared to 111In-DTPA-octreotide in patients with neuroendocrine tumours: the LACOG 0214 study.

99mTc-EDDA/HYNIC-TOC is an easily available and cheaper radionuclide that could be used for somatostatin-receptor-based imaging of neuroendocrine tumours (NETs). We aimed to evaluate the diagnostic performance of 99mTc-EDDA/HYNIC-TOC compared to111In-DTPA-octreotide in patients (pts) with NETs. We performed a prospective diagnostic study including pts with biopsy-confirmed NET and at least one visible lesion at conventional imaging. Two independent nuclear medicine physicians evaluated pts who underwent 99mTc and 111In scans and images. The primary outcome was comparative diagnostic accuracy of 99mTc and 111In. Secondary outcomes include safety. Nine pts were included and performed 14 paired scans. Overall, 126 lesions were identified. 99mTc demonstrated superior sensitivity both when all images were analysed (93.7, 95% CI 88.1% - 96.8% versus 74.8%, 95% CI 66.6 - 81.6%, p < 0.001) and when liver-specific images were analysed (97.8%, 95% CI 92.7% - 99.5% versus 85.1%, 95% CI 76.6% - 91.0%, p < 0.001). 99mTc was also associated with a lower negative likelihood ratio (LR) (0.002, 95% CI 0.009 - 0.1 versus 0.19, 95% CI 0.12 - 0.42, p = 0.009) when evaluating hepatic lesions. Adverse events happened in 3 pts after 111In and in 2 pts after 99mTc, all grade 1. The 99mTc demonstrated a higher sensitivity overall and a better negative LR in liver-specific images compared to 111In in pts with NETs. Our findings suggest that 99mTc is an alternative to 111In and is especially useful in ruling out liver metastases. NCT02691078.

Somatostatin Receptor-PET/CT/MRI of Head and Neck Neuroendocrine Tumors.

Due to its high sensitivity, somatostatin receptor-PET may detect smaller lesions and more extensive disease than contrast-enhanced MR imaging, while the superior spatial resolution of MR imaging enables lesions to be accurately localized. We compared results of somatostatin receptor-PET/MRI with those of MR imaging alone and assessed the added value of vertex-to-thigh imaging for head and neck neuroendocrine tumors. Somatostatin receptor-PET/CT was acquired as limited brain or head and neck imaging, with optional vertex-to-thigh imaging, following administration of 64CU/68GA DOTATATE. Somatostatin receptor-PET was fused with separately acquired contrast-enhanced MR imaging. DOTATATE activity was classified as comparable, more extensive, and/or showing additional lesions compared with MR imaging. Vertex-to-thigh findings were classified as positive or negative for metastatic disease or incidental. Thirty patients (with 13 meningiomas, 11 paragangliomas, 1 metastatic papillary thyroid carcinoma, 1 middle ear neuroendocrine adenoma, 1 external auditory canal mass, 1 pituitary carcinoma, 1 olfactory neuroblastoma, 1 orbital mass) were imaged. Five had no evidence of somatostatin receptor-positive lesions and were excluded. In 11/25, somatostatin receptor-PET/MRI and MR imaging were comparable. In 7/25, somatostatin receptor-PET/MRI showed more extensive disease, while in 9/25, somatostatin receptor-PET/MRI identified additional lesions. On vertex-to-thigh imaging, 1 of 17 patients was positive for metastatic disease, 8 of 17 were negative, and 8 of 17 demonstrated incidental findings. Somatostatin receptor-PET detected additional lesions and more extensive disease than contrast-enhanced MR imaging alone, while vertex-to-thigh imaging showed a low incidence of metastatic disease. Somatostatin receptor-PET/MRI enabled superior anatomic delineation of tumor burden, while any discrepancies were readily addressed. Somatostatin receptor-PET/MRI has the potential to play an important role in presurgical and radiation therapy planning of head and neck neuroendocrine tumors.

Implementation of xSPECT, xSPECT bone and Broadquant from literature, clinical survey and innovative phantom study with task-based image quality assessment

ObjectiveFrom patient and phantom studies, we aimed to highlight an original implementation process and share a two-years experience clinical feedback on xSPECT (xS), xSPECT Bone (xB) and Broadquant quantification (Siemens) for 99mTc-bone and 177Lu-NET (neuroendocrine tumors) imaging. MethodsFirstly, we checked the relevance of implemented protocols and Broadquant module on the basis of literature and with a homogeneous phantom study respectively. Then, we described xS and xB behaviours with reconstruction parameters (10i-0mm to 40i-20mm) and optimized the protocols through a blinded survey (7 physicians). Finally, the preferred 99mTc-bone reconstruction was assessed through an IEC NEMA phantom including liquid bone spheres. Conventional SNR, CNR, spatial resolution, Q.%error, and recovery curves; and innovative NPS, TTF and detectability score d’ were performed (ImQuest software). We also sought to review the adoption of these tools in clinical routine and showed the potential of quantitative xB in the context of theranostics (Xofigo®). ResultsWe showed the need of optimization of implemented reconstruction algorithms and pointed out a decay correction particularity with Broadquant. Preferred parameters were 1s-25i-8mm and 1s-25i-5mm for xS/xB-bone and xS-NET imaging respectively. The phantom study highlighted the different image quality especially for the enhanced spatial resolution xB algorithm (1/TTF10%=2.1 mm) and showed F3D and xB shared the best performances in terms of image quality and quantification. xS was generally less efficient. ConclusionsQualitative F3D still remains the clinical standard, xB and Broadquant offer challenging perspectives in theranostics. We introduced the potential of innovative metrics for image quality analysis and showed how CT tools should be adapted to fit nuclear medicine imaging.

In silico Study on the Binding Interactions of SSTA and 18F-SSTA Towards Somatostatin Receptor Subtype 2.

Somatostatin analogs (SSTAs) are versatile drugs that target a group of proteins known as somatostatin receptors. SSTAs are used for the treatment and PET-molecular imaging of Neuro Endocrine Tumors (NET), for they are labeled with the radionuclide 18F, a positron emitter radionuclide. The aim of this work was to theoretically study the binding interactions of SSTA labeled with 18F (half-life of 109.7 min) and somatostatin receptor subtype 2. As the labeling of SSTA with 18F required the use of a prosthetic group, a hydrophilicity enhancer, and a linker, the influence of these traits on the interactions of 18F-SSTA with the SSTR-2 binding site was studied. The binding modes of 18F-labeled analogues with SSTR-2 were studied by using protein homology modelling, non-equilibrium molecular dynamics, and molecular docking calculations, by means of three docking software: MVD, MOE, and VINA. The results showed the main role of Asp122, Asn276, Phe272 and Phe294 from the SSTR-2 binding site, which form interactions with residues Lys, Trp, Tyr, and Thr from 18F-labeled somatostatin analogues. The interaction between Lys (from 18F-SSTA) and Asp122 (from SSTR-2) was identified as the most energetic and considered the one that drives the binding between 18F-SSTA and SSTR-2 (the anchor interaction). Despite the presence of prosthetic groups, linkers, and hydrophilicity enhancers, all the studied 18F-SSTA formed the anchor interaction. The trend in the results agreed with the experimental reports, identifying the main role of Asp122 in the binding of somatostatin-14 to SSTR-2.

Perspective of molecular imaging and peptide receptor radionuclide therapy in pancreatic neuroendocrine tumors: where do we stand?

The clinical use of nuclear medicine imaging and therapy in pancreatic neuroendocrine tumors has been greatly strengthened since the approval of 68Ga-DOTATATE and 177Lu-DOTATATE. However, many aspects are still under discussion. In this 2-part article, we aim to collect and discuss current evidence of molecular imaging and peptide receptor radionuclide therapy (PRRT) in pancreatic neuroendocrine tumor. In the first part, we will address some critical aspects of 68Ga-SSAs imaging, including diagnostic efficacy, recurrence detection and follow-up, patient selection for PRRT, and pitfalls in image interpretation. Besides, we will also briefly discuss the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography, special imaging strategy in regard to insulinoma, and the status of radiolabeled somatostatin receptor antagonist. In the second part, we aim to review the current evidence of PRRT in pancreatic neuroendocrine tumor, focusing on efficacy and safety in particular. We will also introduce the recent development of PRRT, including PRRT in high-grade neuroendocrine neoplasms, retreatment PRRT, upfront PRRT, PRRT in the setting of neoadjuvant therapy and conversion therapy, combination therapies with PRRT, PRRT with αradionuclides, and PRRT with antagonists.

Rationalizing the Binding Modes of PET Radiotracers Targeting the Norepinephrine Transporter

A new PET radiotracer 18F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure-activity relationships (SARs) of NET-targeting radiotracers have rarely been performed. Without changing the phenethylguanidine pharmacophore and 3-fluoropropyl moiety that is crucial for easy labeling, six new analogs of 18F-AF78 with different meta-substituents on the benzene-ring were synthesized and evaluated in a competitive cellular uptake assay and in in vivo animal experiments in rats. Computational modeling of these tracers was established to quantitatively rationalize the interaction between the radiotracers and NET. Using non-radiolabeled reference compounds, a competitive cellular uptake assay showed a decrease in NET-transporting affinity from meta-fluorine to iodine (0.42 and 6.51 µM, respectively), with meta-OH being the least active (22.67 µM). Furthermore, in vivo animal studies with radioisotopes showed that heart-to-blood ratios agreed with the cellular experiments, with AF78(F) exhibiting the highest cardiac uptake. This result correlates positively with the electronegativity rather than the atomic radius of the meta-substituent. Computational modeling studies revealed a crucial influence of halogen substituents on the radiotracer-NET interaction, whereby a T-shaped π-π stacking interaction between the benzene-ring of the tracer and the amino acid residues surrounding the NET binding site made major contributions to the different affinities, in accordance with the pharmacological data. The SARs were characterized by in vitro and in vivo evaluation, and computational modeling quantitatively rationalized the interaction between radiotracers and the NET binding site. These findings pave the way for further evaluation in different species and underline the potential of AF78(F) for clinical application, e.g., cardiac innervation imaging or molecular imaging of neuroendocrine tumors.

Evaluation of Re/99mTc-labeled somatostatin receptor-targeting peptide complexes synthesized via direct metal cyclization

Abstract With interest in the development of somatostatin receptor (SSTR) targeting agents for potential application in diagnostic SPECT imaging (99mTc) or Peptide Radionuclide Receptor Therapy (PRRT, 186Re or 188Re) of neuroendocrine tumors, we present herein 99mTc/Re (radio)complexes synthesized by the integrated (radio)labeling approach of peptide cyclization via metal complexation. In particular, we utilized the potent SSTR2 peptide antagonist sequence DOTA-4-NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH2 (DOTA-sst2-ANT) and report the syntheses and in vitro evaluations of its respective [99mTc]Tc/Re-cyclized peptides ([99mTc]Tc/Re-cyc-DOTA-sst2-ANT). The Re-cyc-DOTA-sst2-ANT complex was synthesized via an on-resin Re(V)-cyclization reaction using the ReOCl3(PPh3)2 precursor and consisted of three isomers characterized by LC–ESI-MS. The [99mTc]Tc-cyclized analogue was prepared via a ligand exchange reaction of the [99mTc][TcO]3+ core through a [99mTc]Tc-glucoheptonate intermediate with linear DOTA-sst2-ANT and was characterized by comparative HPLC studies against Re-cyc-DOTA-sst2-ANT. Good in vitro binding affinity was demonstrated in SSTR-expressing cells (AR42J) by the Re-cyc-DOTA-sst2-ANT major isomer, similar to the potent binder Lu-DOTA-sst2-ANT, in which the Lu metal was complexed by the bifunctional chelator DOTA versus via peptide cyclization. [99mTc]Tc-cyc-DOTA-sst2-ANT was obtained in high radiochemical yield, also with an elution pattern of three isomers observed by HPLC analysis, which were comparable yet not identical to those of Re-cyc-DOTA-sst2-ANT. The [99mTc]Tc-tracer complex was shown to be hydrophilic, and stability studies at 4 h demonstrated that it remained intact in both PBS and in rat serum, with low non-specific rat serum protein binding, while exhibiting more moderate stability in 1 mM cysteine. These findings demonstrate that direct Re/[99mTc]Tc-cyclization of DOTA-sst2-ANT is feasible and may be used as an alternative approach to the bifunctional chelate labeling strategy. However, given that the non-radioactive (Re) and radiotracer (99mTc) analogues are not identical and both form isomeric products in equilibrium, additional design modifications will be necessary prior to in vivo application of [99mTc]Tc/Re-cyc-DOTA-sst2-ANT.

Clinical significance of atypical 68Ga-DOTATOC prostatic uptake on PET/CT: A ten-year review.

Gallium-68-DOTA-D-Phe1-Try3-Octreotide (68Ga-DOTATOC) is a radiolabeled somatostatin receptor (SSTR) analog that is widely used in the imaging of neuroendocrine tumors (NET). Benign and malignant prostate tumors have been observed to express SSTR. Diffuse symmetric DOTATOC uptake in the prostate is a normal positron emission tomography (PET) finding. The aim of this study was to evaluate the frequency and clinical significance of incidental atypical prostatic uptake in men undergoing 68Ga-DOTATOC PET/computed tomography(CT). A retrospective review of consecutive male patients who underwent 68Ga-DOTATOC PET/CT studies at Aalborg University Hospital, Denmark, from November 2010 to April 2020 was performed. Positron emission tomography/CT reports were searched for text words or phrases indicating incidental atypical prostatic uptake. In the resulting cohort, PET/CT were re-evaluated, and DOTATOC uptake in the prostate gland was categorized as focal, diffuse or mixed. The intensity of the uptake was visually graded using the Krenning visual score. Follow-up was based on all available clinical, biochemical, imaging, and pathology follow-up. A total of 178 male patients underwent 193 68Ga-DOTATOC PET/CT scans. Incidental atypical uptake of 68Ga-DOTATOC on PET/CT in the prostatic bed was observed in eight patients (4.5%) (mean age 67 years, range 58-85 years). Six patients (75%) had diffuse uptake; two (25%) patients had focal uptake. Four patients out of eight with incidental findings (50%) had uptake less than or equal to that of the liver (Krenning score 2); four patients (50%) had uptake greater than that of the liver (score 3). All patients had measurements of serum prostate-specific antigen and were referred for urological evaluation. Five patients (62%) underwent a transrectal ultrasound, and three required a biopsy of the prostate. No cases of prostate malignancy (including prostatic cancer) were diagnosed. During a 10-year period, we found that 4.5% of men exhibited prostate incidentalomas on 68Ga-DOTATOC PET/CT. No malignancy was found in the prostate in this population. Our data indicate absent malignancy among incidental 68Ga-DOTATOC findings in the prostate.

Al[18F]F-NOTA-Octreotide Is Comparable to [68Ga]Ga-DOTA-TATE for PET/CT Imaging of Neuroendocrine Tumours in the Latin-American Population.

PET imaging of neuroendocrine tumours (NET) is well established for staging and therapy follow-up. The short half-life, increasing costs, and regulatory issues significantly limit the availability of approved imaging agents, such as [68Ga]Ga-DOTA-TATE. Al[18F]F-NOTA-Octreotide provides a similar biodistribution and tumour uptake, can be produced on a large scale and may improve access to precision imaging. Here we prospectively compared the clinical utility of [68Ga]Ga-DOTA-TATE and Al[18F]F-NOTA-Octreotide in the Latin-American population. Our results showed that in patients with stage IV NETs [68Ga]Ga-DOTA-TATE presents higher physiological uptake than Al[18F]F-NOTA-Octreotide in the liver, hypophysis, salivary glands, adrenal glands (all p &lt; 0.001), pancreatic uncinated process, kidneys, and small intestine (all p &lt; 0.05). Nevertheless, despite the lower background uptake of Al[18F]F-NOTA-Octreotide, comparative analysis of tumour-to-liver (TLR) and tumour-to-spleen (TSR) showed no statistically significant difference for lesions in the liver, bone, lymph nodes, and other tissues. Only three discordant lesions in highly-metastases livers were detected by [68Ga]Ga-DOTA-TATE but not by Al[18F]F-NOTA-Octreotide and only one discordant lesion was detected by Al[18F]F-NOTA-Octreotide but not by [68Ga]Ga-DOTA-TATE. Non-inferiority analysis showed that Al[18F]F-NOTA-Octreotide is comparable to [68Ga]Ga-DOTA-TATE. Hence, our results demonstrate that Al[18F]F-NOTA-Octreotide provided excellent image quality, visualized NET lesions with high sensitivity and represents a highly promising, clinical alternative to [68Ga]Ga-DOTA-TATE.