New developments in the diagnosis of neuroendocrine tumors

Neuroendocrine neoplasms (NENs) comprise a rare group of heterogenous neoplasms that originate from cells with a neuroendocrine phenotype and can arise in almost every organ or region of the body [1]. They display a variable biological behavior; in fact, in some patients the disease may be stable for years, whereas in others, it might be very aggressive [2]. NENs are often divided into two subgroups in terms of cell morphology, genetics, and prognosis.Well-differentiated, low-proliferating neuroendocrine tumors (NETs) (low to intermediate grade indolent tumors) and poorly dif­ferentiated, highly proliferating neuro­endocrine carcinoma (NECs) (high grade ­aggressive carcinomas) [3]. The gastro­intestinal tract (70 %) and the lung (20 %) are the most frequent primary affected sites [4]. Overall, 90 % of NENs express ­somatostatin receptors (SSTRs) on their cell surface [2].

68Ga-DATA5m-LM4: first-in-human study

As first SSTR agonist, 68Ga-DOTATATE was already granted approval in several European countries and by the FDA in 2016 as a novel diagnostic imaging agent for the detection of rare NETs. Furthermore, in 2018 177Lu-DOTATATE was approved for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [5]. Notably, SSTR-antagonists demonstrated to target a greater number of binding sites on tumor cells than SSTR-agonists, due to their ability to bind to SSTR independently of receptor activation [6, 7]. Especially, in patients with low or no SSTR agonist binding, 177Lu-DOTA-LM3 has proven its effectiveness and safety in the treatment of metastatic NENs. This is achieved by offering a favorable biodistribution and delivering higher tumor radiation doses than SSTR agonists [8]. A first-in-human study presented at EANM 2023 aimed at evaluating the feasibility of the innovative kit-type SSTR antagonist 68Ga-DATA5m-LMA for PET imaging in metastatic NETs [9].

The objectives of this trial were to assess the safety, biodistribution and diagnostic efficacy of 68Ga-DATA5m-LMA. In total, 27 patients (70 % male; mean age, 61 years) showing histopathologically confirmed well-differentiated NETs underwent 68Ga-DATA5m-LMA PET/CT imaging for staging and restaging or patient selection for PRRT. The mean intravenous injection activity was 151 ± 54 MBq and the average uptake time 76 min (range, 50-128). The normal organ uptake of 68Ga-DATA5m-LMA was significantly lower, particularly in the liver as compared to 68Ga-DOTATATE (3.90 ± 0.88 vs. 9.12 ± 3.64;
p < 0.000001). Compared to 68Ga-DOTATOC, there was a significantly lower uptake of 68Ga-DATA5m-LMA reported in the liver and spleen, too.

Regarding NET patients, there was a very high uptake reported in the tumor lesions (standardized uptake value, ­SUVmax, 44.5 ± 36.2; range, 12.3-167.9). The calculated tumor-to-background ratios (TBRs) reached 20.32 ± 19.97 in healthy liver parenchyma, 4.30 ± 3.03 in the kidneys and 38.63 ± 35.97 in the blood. The authors reported that with 68Ga-DATA5m-TOC PET/CT, further small CT and/or MRI “invisible” lesions were identified in different organs of NET patients. The advantageous imaging characteristics of the novel SSTR antagonist 68Ga-DATA5m-LMA, which include higher tumor contrast and lower uptake in normal tissues compared to SSTR agonists, along with its kit-type production features, establish 68Ga-DATA5m-LMA as a potential new powerful radiopharmaceutical for diagnosing NETs and detecting very small metastases.

Head-to head comparison between [18F]-AlF-NOTA-LM3 and 68Ga-DOTATATE

SSTRs on the cell membrane of NETs are promising candidates both as diagnostic tools (γ or β-emissions) or for therapeutic purposes (β-emissions) [10]. Due to their high specificity and sensitivity, 68Ga-­labelled SSTR agonist agents are widely used for imaging of NETs. However, SSTR antagonists have already shown their ­superiority over SSTR agonists in terms of lower physiological uptake and higher detection rates [9]. Specifically, 18F-­labelled tracers have a longer half-life and a lower positron energy, which, in turn, enables better image quality [11]. At this year’s EANM, Meixi Liu presented a study aiming at prospectively assessing the safety and biodistribution of [18F]-AlF-NOTA-LM3 and to compare its diagnostics efficacy with the gold-standard 68Ga-DOTATATE [12].

The patients included in the study had histologically confirmed, well-differentiated NETs (grade 1 or grade 2), with no long-acting somatostatin analog treatment within the past four weeks and no PRRT therapy within the last eight weeks. Patients underwent two whole-body PET/CT scans: one 60 to 90 minutes after the intravenous infusion of [18F]-AlF-­NOTA-LM3 (3.7-5.55 MBq/kg) and the other conducted 60 minutes after the intravenous infusion of 68Ga-­DOTATATE (111-185 MBq). Both scans were conducted within a week, with a minimum of 24 hours between the two scans. Of note, the first eight patients receiving [18F]-AlF-NOTA-LM3 underwent dynamic PET scans.

Out of 17 patients screened, 15 were enrolled in this trial. The median age was 52 years and 60 % were males. The primary sites of malignant lesions were as follows: the pancreas (46.7 %), the duodenum (20.0 %), the lungs and the rectum (6.7 % each). Most patients (60 %) had grade 2 NET tumors. In terms of safety outcomes, a significant decrease in heart rate was observed two hours after injection (p = 0.006), with no other signifi­cant alterations in vital signs reported.

A high physiological uptake of [18F]-AlF-NOTA-LM3 was observed in pituitary and adrenal glands, as well as in the spleen. Compared to 68Ga-DOTATATE, [18F]AlF-NOTA-LM3 showed a significant lower physiological uptake in the liver (2.9 vs. 6.2), the spleen (6.9 vs. 20.2), the pancreas (1.8 vs. 2.8), the stomach (2.7 vs. 6.2), the small intestine (2.6 vs. 5.8), the renal cortex (10.3 vs. 12.2) but a significant higher uptake in the blood (1.6 vs. 0.5) and the lung (0.6 vs. 0.3). In 78 % of patients with liver metastases, [18F]AlF-NOTA-LM3 detected more lesions (275 vs. 219; p = 0.028) in comparison to 68Ga-­DOTATATE. Similarly, in 76 % of patients with lymph node metastases, [18F]AlF-NOTA-LM3 revealed more lesions (21 vs. 14; p = 0.020). Otherwise, both tracers were comparable regarding primary ­tumor and bone lesion detection, as well as tumor specific uptake parameters (SUVmax). Moreover, a higher TBR of liver, pancreatic and bone metastases was observed with [18F]AlF-NOTA-LM3 (Table 1).

The authors concluded that [18F]AlF-NOTA-LM3 is a promising SSTR antagonist, exhibiting a superior detection rate and a better performance in detecting liver and lymph node lesions compared to the standard 68Ga-DOTATATE. Furthermore, [18F]AlF-NOTA-LM3 de­mon­strated good safety, with no AEs ­related to the radiopharmaceutical ­reported. Consequently, in the authors’ opinion, it represents a valuable new option for imaging NETs.

Table 1 Comparison between [18F]AlF-NOTA-LM3 and 68Ga-DOTATATE in terms of number of metastases, SUVmax and TBR.

[68Ga]Ga-DATA5m-LM4 versus [68Ga]Ga-DOTANOC PET/CT

An interim analysis of a retrospective study comparing the diagnostic efficacy of the SSRT ligand antagonist [68Ga]Ga-DATA5m-LM4 with [68Ga]Ga-­DOTANOC in terms of detection of primary tumors and metastases in histologically proven GEP-NET patients was presented by Rahul Viswanathan at this year’s EANM [13].

Overall, 29 patients (52 % men) with a mean age of 49 years (range, 25-67) were enrolled in this study. Thirteen patients had low-grade (G1) NETs, seven patients had intermediate grade (G2) NETs, and nine patients had high grade (G3) NETs. In total, 51.7 % of patients had distant ­metastases and 48.2 % a locally advanced disease. Cross-sectional diagnostic CT confirmed 390 lesions (25 primary tumors, 261 liver metastases, 69 lymph node metastases, 28 bone metastases and 7 lung metastases). Patients received a mean injection dose of 99.9 MBq/kg of [68Ga]Ga-DOTANOC or 159.1 MBq/kg of [68Ga]Ga-DATA5m-LM4. The lesion-­based sensitivity reached 84.0 % for [68Ga]Ga-DATA5m-LM4 PET and 66.6 % for [68Ga]Ga-DOTANOC PET (p < 0.0001). A higher number of metastases were detected with [68Ga]Ga-DATA5m-LM4 compared to [68Ga]Ga-DOTANOC in all primary tumors and lesions analyzed, especially in liver (87 % vs. 67 %; p < 0.0001) and bone metastases (100 % vs. 32 %; p < 0.0001). Similarly, the qualitative and quantitative (SUV corrected for lean body mass, SULmax/SULavg) analyses revealed a significant higher uptake ­(SULmax and SULavg) of [68Ga]Ga-­DATA5m-LM4 compared to [68Ga]Ga-DOTANOC (p < 0.05) in liver and bone metastases.

In conclusion, the [68Ga]Ga-­DATA5m-LM4 radiotracer has demonstrated encouraging interim results in patients with GEP-NETs. Nevertheless, further analysis in clinical trials with larger sample sizes are warranted.

TECANT: phase 1 study with 99mTc-labelled SSTR antagonist

NENs, which have been traditionally considered as rare diseases, are often diagnosed at a late stage due to the absence of specific symptoms [1]. Hence, early detection plays a crucial role in the management of NEN patients, influencing therapy selection and disease monitoring. At EANM 2023, Marta Opalińska presented the first results of the multicenter phase 1 TECANT trial (NCT05871320) which aims to initiate a clinical feasibility study with a novel 99mTc-labelled SSTR2-antagonist as a sensitive probe to assess the SSTR status in NEN patients, and to develop a robust, reproducible quantitative imaging method [14]. After conducting comprehensive preclinical in vitro and in vivo studies, [99mTc]Tc-TECANT1 was selected among two potential candidates due to its longer tumor residence time, as well as lower kidney and liver uptake. In total, ten patients with advanced SSTR-positive NENs underwent single photon emission computed tomography (SPECT) scan combined to CT scans. The administration of [99mTc]Tc-TECANT1 ­resulted in a rapid distribution with predominant renal excretion. No related ­adverse events were observed. [99mTc]Tc-TECANT1 tumor uptake was visible as early as five minutes following administration and retained 24 hours post-injection. The highest TBRs was detected four hours post-injection. Moreover, the contrast in the images was superior to those obtained with a 68Ga-SSTR agonist for most of the analyzed lesions.

As [99mTc]Tc-TECANT1 – a SSTR antagonist – has demonstrated high-quality imaging results along with a favorable toxicological and pharmacological profile, this novel radionuclide holds the ­potential to become an innovative tool in the diagnostic and therapeutic pathways for patients with NENs.


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