Somatostatin receptor (sstr) scintigraphy for imaging and sstr analogs for treatment have been used for more than 20 y. An important improvement in recent years was the introduction of peptide receptor radionuclide therapy with radiolabeled sstr agonists, such as [⁹⁰Y-DOTA⁰,Tyr³]octreotide or [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotide (⁹⁰Y- or ¹⁷⁷Lu-DOTATOC, respectively) and [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-DOTATATE). PET/CT with ⁶⁸Ga-labeled sstr agonists, such as ⁶⁸Ga-DOTATOC, ⁶⁸Ga-DOTATATE, and [⁶⁸Ga-DOTA,1-Nal³]octreotide (⁶⁸Ga-DOTANOC), plays an important role in staging and restaging neuroendocrine tumors. Most importantly, sstr scintigraphy and sstr PET/CT can distinguish patients who will qualify for and benefit from peptide receptor radionuclide therapy. This characteristic of sstr targeting is important because it allows a personalized treatment approach (theranostic approach). Until recently, it was thought that internalization of the radiolabeled agonist was mandatory for sstr-mediated imaging and therapy. It was Ginj et al. who proposed in 2006 the paradigm shift that radiolabeled sstr antagonists may perform better than agonists despite the lack of internalization. Despite the rather limited number of head-to-head comparisons of sstr antagonists and agonists, the superiority of sstr antagonists was demonstrated in several cases. From a small library of sstr antagonists, the analog JR11 (Cpa-c[d-Cys-Aph(Hor)-d-Aph(Cbm)-Lys-Thr-Cys]-d-Tyr-NH₂), an antagonist with selectivity for sstr subtype 2, showed the best overall characteristics for sstr subtype 2 targeting and was therefore selected for clinical translation. JR11 is under clinical development as a PET imaging agent when labeled with ⁶⁸Ga (⁶⁸Ga-NODAGA-JR11 or ⁶⁸Ga-OPS202) and as a therapeutic agent when labeled with ¹⁷⁷Lu (¹⁷⁷Lu-DOTA-JR11 or ¹⁷⁷Lu-OPS201). In this article, we discuss the development and current status of radiolabeled sstr antagonists. Evidence based on preclinical work, on quantitative in vivo autoradiography of human tumor slices, and on human data now supports a shift to sstr antagonists.

Preclinical and clinical studies have indicated that somatostatin receptor (sst)-expressing tumors demonstrate higher uptake of radiolabeled sst antagonists than of sst agonists. In 4 consecutive patients with advanced neuroendocrine tumors, we evaluated whether treatment with (177)Lu-labeled sst antagonists is feasible. After injection of approximately 1 GBq of (177)Lu-DOTA-[Cpa-c(DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys)-DTyr-NH2] ((177)Lu-DOTA-JR11) and (177)Lu-DOTATATE, 3-dimensional voxel dosimetry analysis based on SPECT/CT was performed. A higher tumor-to-organ dose ratio for (177)Lu-DOTA-JR11 than for (177)Lu-DOTATATE was the prerequisite for treatment with (177)Lu-DOTA-JR11. Reversible minor adverse effects of (177)Lu-DOTA-JR11 were observed. (177)Lu-DOTA-JR11 showed a 1.7-10.6 times higher tumor dose than (177)Lu-DOTATATE. At the same time, the tumor-to-kidney and tumor-to-bone marrow dose ratio was 1.1-7.2 times higher. All 4 patients were treated with (177)Lu-DOTA-JR11, resulting in partial remission in 2 patients, stable disease in 1 patient, and mixed response in the other patient. Treatment of neuroendocrine tumors with radiolabeled sst antagonists is clinically feasible and may have a significant impact on peptide receptor radionuclide therapy.

Small benign insulinomas are hard to localise, leading to difficulties in planning of surgical interventions. We aimed to prospectively assess the insulinoma detection rate of single-photon emission CT in combination with CT (SPECT/CT) with a glucagon-like peptide-1 receptor avid radiotracer, and compare detection rates with conventional CT/MRI techniques. In our prospective imaging study, we enrolled adults aged 25-81 years at centres in Germany, Switzerland, and the UK. Eligible patients had proven clinical and biochemical endogenous hyperinsulinaemic hypoglycaemia and no evidence for metastatic disease on conventional imaging. CT/MRI imaging was done at referring centres according to standard protocols. At three tertiary nuclear medicine centres, we used whole body planar images and SPECT/CT of the abdomen up to 168 h after injection of (111)In-[Lys40(Ahx-DTPA-(111)In)NH2]-exendin-4 ((111)In-DTPA-exendin-4) to identify insulinomas. Consenting patients underwent surgery and imaging findings were confirmed histologically. Between Oct 1, 2008, and Dec 31, 2011, we recruited 30 patients. All patients underwent (111)In-DTPA-exendin-4 imaging, 25 patients underwent surgery (with histological analysis), and 27 patients were assessed with CT/MRI. (111)In-DTPA-exendin-4 SPECT/CT correctly detected 19 insulinomas and four additional positive lesions (two islet-cell hyperplasia and two uncharacterised lesions) resulting in a positive predictive value of 83% (95% CI 62-94). One true negative (islet-cell hyperplasia) and one false negative (malignant insulinoma) result was identified in separate patients by (111)In-DTPA-exendin-4 SPECT/CT. Seven patients (23%) were referred to surgery on the basis of (111)In-DTPA-exendin-4 imaging alone. For 23 assessable patients, (111)In-DTPA-exendin-4 SPECT/CT had a higher sensitivity (95% [95% CI 74-100]) than did CT/MRI (47% [27-68]; p=0.011). (111)In-DTPA-exendin-4 SPECT/CT could provide a good second-line imaging strategy for patients with negative results on initial imaging with CT/MRI. Oncosuisse, the Swiss National Science Foundation, and UK Department of Health.

Radiolabeled somatostatin receptor (sst) agonists are integral to the diagnosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), but detection rates, especially of liver metastases, remain disappointing even with PET/CT. ⁶⁸Ga-OPS202 (⁶⁸Ga-NODAGA-JR11), a novel radiolabeled sst antagonist with a high affinity for sst₂, has the potential to perform better than sst agonists. Here we present the results of the Phase II component of a Phase I/II study, which evaluated the sensitivity of ⁶⁸Ga-OPS202 PET/CT compared with the reference compound, ⁶⁸Ga-DOTATOC (sst agonist). Methods: Patients received a single intravenous administration of ⁶⁸Ga-DOTATOC (15 µg peptide) and ⁶⁸Ga-OPS202 (15 µg peptide at visit 1; 50 µg peptide at visit 2) with an activity of 150 MBq. Whole-body PET/CT acquisitions were performed 1 h post injection on the same calibrated PET/CT scanner. Diagnostic efficacy measures were compared against contrast medium-enhanced CT or MRI as gold standard. Two independent blinded experts read the scans and both outcomes were combined for analysis. Results: Twelve consecutive patients with G1 or G2 GEP-NETs took part in this prospective study. Image contrast for matched malignant liver lesions was significantly higher for ⁶⁸Ga-OPS202 scans than for the ⁶⁸Ga-DOTATOC scan: median of the mean [interquartile] tumor-to-normal-liver SUV_max ratios for 15 µg and 50 µg ⁶⁸Ga-OPS202 (5.3 [2.9 – 5.7] and 4.3 [3.4 – 6.3], respectively) were significantly higher than for ⁶⁸Ga-DOTATOC (1.9 [1.4 – 2.9]; P = 0.004 and P = 0.008, respectively). The higher tumor-to-background ratio of ⁶⁸Ga-OPS202 resulted not only in a higher detection rate of liver metastases, but also in a significantly higher lesion-based overall sensitivity with the antagonist than with ⁶⁸Ga-DOTATOC PET/CT: 94% and 88% for 50 µg and 15 µg ⁶⁸Ga-OPS202 and 59% for 15 µg ⁶⁸Ga-DOTATOC, respectively (p<0.001). Positive predictive values (PPVs) for ⁶⁸Ga-OPS202 PET/CT and ⁶⁸Ga DOTATOC PET/CT were similar (approximately 98%). There were no significant differences between the two ⁶⁸Ga-OPS202 peptide doses in terms of image contrast, sensitivity or PPVs, indicating a high reproducibility. Conclusion: Preliminary efficacy data from this Phase II study indicate that ⁶⁸Ga-OPS202 has high sensitivity for the detection of GEP-NETs. Further studies in larger patient populations are warranted.

Radiolabeled somatostatin receptor (sstr) antagonists have shown in vivo higher uptake in sstr-expressing tumors than agonists. In this pre-clinical study the sstr2-antagonist OPS201 (DOTA-JR11; DOTA-[Cpa-c(DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys)-DTyr-NH2]) labeled with ¹⁷⁷Lu, ⁹⁰Y and ¹¹¹In was compared with the sstr2-agonist ¹⁷⁷Lu-DOTA-TATE. Methods: Biodistribution, pharmacokinetics, single-photon emission computed tomography/computed tomography (SPECT/CT) and dosimetry studies were performed to assess the bioequivalence of all radiotracers. Use of escalated peptide mass and nephroprotective agents were systematically investigated. Results: The tumor residence time was 15.6h [13.4-17.7] for ¹⁷⁷Lu-OPS201 (10 pmol) and 6.4h [5.4-7.3] for ¹⁷⁷Lu-DOTA-TATE, resulting in 2.5 times higher tumor dose for the antagonist than for the agonist (0.854 vs 0.333 mGy/MBq for a 4 cm tumor). The overall tumor-to-kidney dose ratio was approximately 24% and 32% higher for ¹⁷⁷Lu-OPS201 than for ⁹⁰Y-OPS201 and ¹⁷⁷Lu-DOTA-TATE, respectively. ¹¹¹In-OPS201 had significantly different biodistribution than ⁹⁰Y-OPS201 and is therefore not a surrogate for ⁹⁰Y-OPS201 dosimetry studies. Importantly, and in contrast to ¹⁷⁷Lu-DOTA-TATE, injection of 10, 200 and 2000 pmol of ¹⁷⁷Lu-OPS201 did not cause any relevant tumor saturation, with tumor uptake 4h post injection (p.i.): 23.9, 24.9 and 18.8 percentage of injected activity per gram of tissue (%IA/g), respectively for the antagonist (p>0.05), as compared to 17.8, 12.0 and 9.9%IA/g for the agonist (p<0.05). Increasing the peptide mass of ¹⁷⁷Lu-OPS201 from 10 to 200 pmol drastically decreased the effective dose from 0.0908 to 0.0184 mSv/MBq and also the uptake in the liver, bone marrow and all sstr2-expressing organs, thus the therapeutic index improved considerably. Lysine, Gelofusine, alone or in combination, significantly reduced the renal dose of ¹⁷⁷Lu-OPS201 compared to the control group, by 45%, 25% and 40%, respectively (p<0.05). The reduction was similar for 10 and 200 pmol, while lysine performed better than Gelofusine. Conclusion: ¹⁷⁷Lu-OPS201 exhibits higher tumor uptake, longer tumor residence time and improved tumor-to-kidney dose ratio compared to ¹⁷⁷Lu-DOTA-TATE and ⁹⁰Y-OPS201. Importantly, the mass-escalation study indicates that an optimized antagonist-mass might further improve the safety window of Peptide Receptor Radionuclide Therapy (PRRT) by reducing liver, bone marrow dose and also the effective dose. Clinical studies are warranted to confirm the efficacy and advantageous toxicity profile of ¹⁷⁷Lu-OPS201.

¹¹¹In-DOTA-exendin-4 SPECT/CT has been shown to be highly efficient in the detection of insulinomas. We aimed at determining whether novel PET/CT imaging with [Nle¹⁴, Lys⁴⁰(Ahx-DOTA-⁶⁸Ga)NH₂]exendin-4 (⁶⁸Ga-DOTA-exendin-4) is feasible and sensitive in detecting benign insulinomas. Methods: ⁶⁸Ga-DOTA-exendin-4 PET/CT and ¹¹¹In-DOTA-exendin-4 SPECT/CT were performed in a randomized cross-over order in 5 patients with endogenous hyperinsulinemic hypoglycemia. Gold standard for comparison was the histological diagnosis after surgery. Results: In 4 patients histological diagnosis confirmed a benign insuIinoma, whereas one patient refused surgery despite a positive ⁶⁸Ga-DOTA-exendin-4 PET/CT scan. In 4 out of 5 patients previously performed conventional imaging (CT/MRI) was not able to localize the insulinoma. ⁶⁸Ga-DOTA-exendin-4 PET/CT correctly identified the insulinoma in 4/4 patients whereas ¹¹¹In-DOTA-exendin-4 SPECT/CT correctly identified the insulinoma in 2/4 patients. Conclusion: These preliminary data suggest that ⁶⁸Ga-DOTA-exendin-4 PET/CT is feasible in detecting hidden insulinomas.