Biodistribution and radiation dose estimates for ⁶⁸Ga-DOTA-JR11 in patients with metastatic neuroendocrine tumors

Abstract

Purpose:

Somatostatin receptor antagonists have shown promise for imaging neuroendocrine tumors (NETs) in preclinical studies, but clinical data is still very limited. In this study, we assess the feasibility of using the novel somatostatin antagonist ⁶⁸Ga-DOTA-JR11 for PET imaging of NETs.

Methods:

Twenty patients with advanced NETs underwent whole-body PET/CT imaging 60 min after injection of 169 MBq (median) ⁶⁸Ga-DOTA-JR11 as part of a prospective study. Volumes of interest were drawn around up to four ⁶⁸Ga-DOTA-JR11-avid lesions per patient (with uptake greater than liver) and standardized uptake values were estimated. Additionally, target-to-normal tissue ratios were calculated. A subset of 6 patients had additional imaging (25-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney and a whole-body PET/CT scan at 30 min post-injection) to determine the time course of tracer distribution and facilitate radiation dose estimates. Absorbed doses were calculated using OLINDA/EXM 1.0.

Results:

In contrast to the known biodistribution of somatostatin receptor agonists, little or no uptake above background was seen in the pituitary gland, spleen, adrenals, and uninvolved liver; e.g., median spleen SUV_mean 1.4 (range: 0.7-1.8), liver SUV_mean 1.1 (0.7-1.9). A total of 42 tumor lesions were analyzed with median SUV_max 13.0 (range: 2.9-94), TNR blood 9.3 (1.8-87), TNR spleen 4.9 (1.9-48), TNR kidney 2.2 (0.52-28), and TNR liver 10.5 (2.3-107). Tumor uptake reached plateau levels by 20-30 min post-injection. The highest absorbed dose estimates (mGy/MBq) to normal tissues were: urinary bladder wall (0.30; SD 0.06) and kidneys (0.050; SD 0.013). The effective dose (ICRP 103) was 0.022 (SD 0.003) mSv/MBq.

Conclusions:

⁶⁸Ga-DOTA-JR11 demonstrated rapid tumor uptake, high tumor/background ratios, and rapid clearance from blood. The low liver background is advantageous and may facilitate detection of liver metastases. Dosimetric data compare favorably with published data for ⁶⁸Ga-DOTATATE and ⁶⁸Ga-DOTATOC.

INTRODUCTION

Neuroendocrine tumors (NETs) represent a heterogenous group of tumors with significantly increasing incidence. For example, gastroenteropancreatic neuroendocrine tumors (GEP-NETs), the largest subgroup of NETs, underwent a striking increase in incidence from 1.0/100,000 in 1973 to 3.65/100,000 in the period 2003-2007 [1] in the US.

Overexpression of somatostatin receptors and specifically the somatostatin receptor subtype 2 (SSTR2) is a common feature of NETs. Radiolabeled, metabolically stable somatostatin receptor binding peptides have been used clinically for imaging of NETs since 1994 [2]. The first FDA-approved agent was ¹¹¹In-octreotide (Octreoscan®). More recently, several ⁶⁸Ga-labeled somatostatin analogues enabling SSTR positron emission tomography/computed tomography (PET/CT) with improved binding affinity and biodistribution have been introduced. One of these agents, ⁶⁸Ga-DOTA-TATE, was FDA-approved in 2016 [3]. All of these imaging agents are somatostatin agonists; i.e., they stimulate the somatostatin receptor and are consequently internalized.

Preclinical studies have indicated that SSTR antagonists bind to significantly more receptor sites than the agonists currently used for peptide receptor radionuclide therapy (PRRT) [4]. This finding was confirmed by quantitative autoradiography of patient-derived tumor samples [5], demonstrating a more than four-fold increase in the ex vivo binding of the somatostatin receptor antagonist ¹⁷⁷Lu-DOTA-BASS compared to the agonist ¹⁷⁷Lu-DOTA-TATE. Wild et al. performed a preliminary clinical study comparing the dosimetry of a ¹⁷⁷Lu-labeled therapeutic SSTR antagonist ¹⁷⁷Lu-DOTA-JR11 with ¹⁷⁷Lu-DOTA-TATE in four patients. In this study, the antagonist demonstrated, on average, a three-fold higher tumor dose and a two-fold higher tumor-to-kidney ratio [6]. PET and biodistribution studies in mice bearing SSTR2-expressing xenografts also demonstrated higher tumor uptake of ⁶⁸Ga-DOTA-JR11 and ⁶⁸Ga-NODAGA-JR11 (⁶⁸Ga-OPS202) than the high-affinity SSTR2 agonist ⁶⁸Ga-DOTA-TATE [7], supporting further clinical evaluation of these imaging agents.

Nicolas et al. recently reported two clinical studies [8, 9] on the use of ⁶⁸Ga-NODAGA-JR11 (⁶⁸Ga-OPS202) to image GEP-NETs. The first of these studies [8] focused on biodistribution, safety, and radiation dosimetry, while the second directly compared the biodistribution of ⁶⁸Ga-NODAGA-JR11 (⁶⁸Ga-OPS202) with that of the SSTR2 agonist ⁶⁸Ga-DOTA-TOC, and found the antagonist to be superior in terms of lesion contrast, detection, and sensitivity [9].

The purpose of this study was to assess the utility of the novel somatostatin antagonist ⁶⁸Ga-DOTA-JR11 for PET imaging of NETs. Patients with advanced NETs and positive ¹¹¹In-pentetreotide (OctreoScan®) scans were imaged with ⁶⁸Ga-DOTA-JR11 prior to PRRT with ¹⁷⁷Lu-DOTA-JR11. Detailed biodistribution and radiation dosimetry was investigated on a subset of these patients.

MATERIALS AND METHODS

Clinical study with ⁶⁸Ga-DOTA-JR11

Under the auspices of a protocol approved by the Institutional Review Board and an Investigational New Drug application approved by the FDA, 20 patients (10 male, 10 females, age: 22-73 years, mean 54 ± 14 years) with progressive, histologically proven, unresectable NETs (18 GEP-NETS, 1 bronchopulmonary neuroendocrine neoplasm, and 1 renal neuroendocrine carcinoma) were imaged with the SSTR2 antagonist ⁶⁸Ga-DOTA-JR11 as a prelude to planned therapy with ¹⁷⁷Lu-DOTA-JR11 after providing written informed consent (trial registration ID NCT02609737). Of these 20 patients, the first 6 had extended imaging to facilitate kinetic analysis and normal tissue radiation dose estimates.

⁶⁸Ga-DOTA-JR11 preparation and administration

⁶⁸Ga-DOTA-JR11 was manufactured by the MSK Radiochemistry and Molecular Imaging Probe Core Facility in compliance with an FDA-approved IND (FDA IND #128,082). The DOTA-JR11 precursor (OctreoPharm, Sciences GmbH, Berlin, Germany) (Supplementary Figure 1) was labeled with ⁶⁸Ga using an EZ-102 reagent kit and a 1.85 GBq/50 mCi ⁶⁸Ga generator supplied by Eckert & Ziegler Radiopharma GmbH, Germany. Briefly, ⁶⁸Ga was eluted from the generator with ~5 ml of 0.1N HCl and adsorbed onto an SCX cartridge. The concentrated ⁶⁸Ga was then eluted from the SCX cartridge using a 5M NaCl/HCl solution directly into the reactor containing 100 μg of DOTA-JR11 peptide and dissolved in sodium acetate buffer, for a final reaction mixture pH of ~3.7. The reaction mixture was heated to 105 °C for 7 minutes to allow for radionuclide incorporation. The reaction mixture was then loaded onto a C18 light SEP-PAK cartridge and washed with normal saline to remove unincorporated radionuclide. Finally, ⁶⁸Ga-DOTA-JR11 was eluted off the purification cartridge with 1 ml of a 1:1 solution of ethanol:water, followed by 9 mL of normal saline, through a 0.22 μm filter, into a sterile, apyrogenic, USP Type I glass vial, sealed with rubber septum and crimped.

The final drug product underwent quality control (QC) testing prior to batch release for patient administration in accordance with acceptance specifications for radiochemical purity, endotoxin content, sterilizing filter integrity, pH, appearance, and radionuclide identity confirmation. Sterility testing was performed post-release.

⁶⁸Ga-DOTA-JR11 was administered to subjects at a planned activity of 185 MBq (5 mCi) ±10% by slow bolus injection.

Toxicity monitoring

Toxicity monitoring consisted of pre-injection and post-scan vital signs (heart rate, blood pressure, body temperature), pulse oximetry, 3-lead electrocardiography, and monitoring of clinical symptoms.

PET/CT imaging with ⁶⁸Ga-DOTA-JR11

All 20 patients underwent whole-body (vertex of skull to mid-thigh) PET/CT imaging (GE PET/CT 710 scanner with time-of-flight) at 60 minutes (mean 64 min; SD 6) post-injection. Patients were asked to void their bladders before imaging. PET scanning was performed in 3-D mode with a 3-min emission time per bed position. A low-dose CT scan (120 kVp, 80 mA tube current, helical pitch 1.5:1; estimated radiation dose 9.0 mGy) was acquired prior to PET imaging for attenuation correction and anatomical localization. Total acquisition time was 18 min or 21 min for 6 or 7 bed positions, respectively. Images were reconstructed using a 700-mm field of view into a 128×128 matrix with iterative ordered subset expectation maximization (OSEM: 16 subsets; 2 iterations) with a 6.4-mm 2D Gaussian post-filter and “heavy” axial 3-point smoothing ([1 2 1]/4). All corrections per manufacturer including CT-based attenuation, scatter, and SharpIR (point spread function correction) were utilized. PET scanner quality assurance as per ACR guidelines, including an ¹⁸F well counter calibration, was performed quarterly. Activity quantification for ⁶⁸Ga PET scans was based on the ¹⁸F calibration and knowledge of ratio of positron yields for ⁶⁸Ga and ¹⁸F (i.e., 0.889 to 0.987).

For the purpose of radiation-absorbed dose estimation, additional images were acquired in the first 6 patients of the 20 accrued (3 female and 3 male). These consisted of a 25-min/19-frame dynamic acquisition initiated at the time of administration and centered on the upper abdomen to include, at least partly, cardiac left ventricle, liver, spleen, and kidney. This was immediately followed at approximately 30 min (mean 34 min; SD 2) post-injection by a whole-body PET/CT scan identical to that acquired at 60 min. Total acquisition time for the dosimetry patient subset was 61-67 min for 6-7 bed positions, respectively.

Image interpretation, lesion detection, and data analysis

The whole-body static PET/CT scans acquired at 60 min post-injection were first interpreted without reference to other imaging modalities. Any lesions with focal radiotracer uptake not explained by physiologic SSTR2 expression were interpreted as metastatic disease.

Volumes of interest (VOI) were generated over lesions using a Hermes imaging workstation (Hermes medical solutions, Chicago, IL, USA). Typically, a value of 40-50% of maximum tracer uptake was used as a threshold but this was guided by interpretation of the CT scan. A total of 42 lesions were analyzed with a maximum of four lesions per patient.

For normal tissues (liver, kidney, spleen, lung, and cardiac left ventricle), regions of interest (ROI) were drawn within organs over at least five consecutive transaxial PET slices and combined to generate VOIs using a Hermes imaging workstation. For liver, ROI were drawn to exclude, as far as possible, enhanced uptake in disease foci.

Tracer uptake was quantified by standardized uptake values (SUV) normalized to patients’ body weight. For lesion VOI, SUV_max and SUV_peak were recorded in addition to SUV_mean. SUV_max referred to the maximum voxel in the VOI, whereas SUV_peak was defined as the mean SUV of the hottest 1 cubic centimeter in the VOI. For normal tissues, only SUV_mean within the VOI was used. In the special case of cardiac left ventricle, the representative value used was the average SUV_max over five slices. We have found this quantity to correspond closely to ex vivo measured blood activity concentration in prior studies.

Comparative lesion uptake was quantified using target-to-normal (TNR) SUV ratios defined as SUV_max (lesion)/SUV (tissue) for blood, spleen, kidney, and liver. As 4 of the 20 patients had prior splenectomy, TNR (spleen) was calculated for only 16 patients.

Absorbed dose calculations

Absorbed radiation doses to normal tissues were estimated in a subset of 6 patients who had additional imaging as described above. Absorbed doses to whole body (WB) and individual organs were calculated based on the combined dynamic and static PET/CT images. Activity concentration-time curves for all organs displaying ⁶⁸Ga-DOTA-JR11 accumulation were generated by VOI analysis. For liver, this curve was for normal (uninvolved) liver. It was assumed that the red marrow activity concentration was equal to that of blood [10]. WB activity-time curves were generated using the 3 points defined by the administered activity (time zero) and the total activities in the two whole-body PET scans. These data were used to calculate mono-exponential biological half-times for WB clearance.

The areas under activity concentration-time curves (AUC) were estimated by trapezoidal integration of the combined data from dynamic and static images with a terminal contribution calculated by extrapolation from the last measured value using the shorter of apparent terminal clearance rate or physical decay. Whole-organ AUCs were estimated by multiplying the activity concentration AUC by organ mass as taken from the OLINDA/EXM 1.0 software application [11]. We did not use patient mass-based rescaling in this study, as the actual patients’ masses did not differ substantially from OLINDA/EXM 1.0 standard values (73.7 kg for male; 56.9 kg for female). The number of disintegrations in normal organs (i.e., residence times) were derived by dividing whole-organ AUC by the administered activity. For urinary bladder contents, residence times were derived using the voiding bladder model built into OLINDA/EXM 1.0, the estimated mono-exponential whole-body biological half-time, and an assumed voiding interval of 1 hour. This relatively short time was deemed appropriate for this short-lived radiopharmaceutical, considering that patients were instructed to void their bladders before the 60-min PET scan and encouraged to hydrate and void frequently thereafter. Residence times for the remainder of body were derived by subtracting all the individually estimated residence times from the whole-body residence time. Absorbed radiation doses to the whole body and various organs were calculated using the OLINDA/EXM 1.0 software application [11]. Subsequently, effective doses were recalculated using the tissue weighting factors promulgated in ICRP Report 103 [12].

RESULTS

⁶⁸Ga-DOTA-JR11 administration and safety

Patient characteristics are summarized in Table 1. All 20 enrolled patients were administered ⁶⁸Ga-DOTA-JR11, underwent at least one whole-body PET/CT, and are included in the analysis. The mean administered activity was 169 MBq (4.6 mCi); range: 137-192 MBq (3.7-5.2 mCi) with a mean radiochemical purity of 99.95% (range: 99-100%). The mean injected peptide mass was 81 μg (range: 60-97 μg) (Supplementary Table 1).

Table 1.

Demographic and clinical characteristics of patients

Patient	Sex	Age (years)	Site of primary	Grade
1	F	22	Small intestine	G2
2	F	29	Pancreas	G2
3	M	61	Pancreas	G1
4	M	42	Stomach	G2
5	M	59	BP	atypical
6	F	56	Pancreas	G2
7	M	73	Rectum	G1
8	M	72	Pancreas	G2
9	F	49	Small intestine	G2
10	F	56	Small intestine	G2
11	F	54	Pancreas	G2
12	F	45	Pancreas	G2
13	F	59	Small intestine	G2
14	F	68	Small intestine	G1
15	M	59	Pancreas	G1
16	F	64	Pancreas	G2
17	M	65	Pancreas	G2
18	M	63	Small intestine	G2
19	M	37	Renal	G3
20	M	44	Pancreas	G1

F: female; M: male; BP: bronchopulmonary; G1: low grade (well differentiated); G2: intermediate grade (moderately differentiated); G3: high grade (poorly differentiated)

Of the 20 patients, 18 experienced no infusion-related symptoms. Two patients with hormone-secreting tumors experienced flushing (G3/2), hypotension (G3/G1), and nausea (G1). Of these, one experienced additional tachycardia (G1), abdominal pain (G2), and diarrhea (G1), requiring injection of 150 μg Octreotide s.c. No significant changes (pre- vs. post-injection) were evident in blood glucose, body temperature, peripheral oxygen saturation, or EKG. No subsequent adverse events were observed in the follow-up period (mean 16 days; range 2-30 days) prior to PRRT.

PET/CT imaging with ⁶⁸Ga-DOTA-JR11

⁶⁸Ga-DOTA-JR11 PET/CT revealed positive lesions in all 20 patients. On visual inspection, images demonstrated favorable biodistribution with little or no uptake in the pituitary, parotid, and salivary glands; thyroid; spleen; adrenals; and uninvolved liver (Figs. 1–3). Quantitative analysis indicated little uptake above blood pool in organs such as spleen (SUV_mean 1.4; range 0.7-1.8; n=16) and uninvolved liver (SUV_mean 1.1; range 0.7-1.9; n=19). Renal uptake was higher with an SUV_mean of 4.5; range 1.3-7.2 (Table 2). The main route of excretion was renal and substantial urinary bladder activity was observed in patients who had whole-body PET/CT images at 30 min post-administration, amounting to a median of 15% of the administered activity (range 12-26%; n=6). However, in most cases, this was significantly reduced at the time of the 60-min image before which patients were instructed to void.

Fig. 1.

Patient with predominant liver involvement. (a) Transverse, coronal, sagittal PET/CT image set at the level of the crosshairs shown in (b) Whole-body maximum-intensity projection images showing the overall distribution of ⁶⁸Ga-DOTA-JR11. Images acquired at 77 minutes post-injection demonstrate the lack of significant uptake in any normal tissues, apart from kidney, and show high uptake in hepatic disease. Minimal activity was present in the urinary bladder following pre-scan voiding. (c) SUV-time curves illustrate the rapid uptake of ⁶⁸Ga-DOTA-JR11 into liver disease with prolonged retention.

Fig. 3.

Panel of five whole-body maximum-intensity projection images acquired at 60 minutes post-injection demonstrating intense focal uptake in metastases and minimal background uptake, resulting in excellent image contrast.

Table 2.

SUV_mean of organs for the 60-min whole-body scan (normal liver, spleen, kidney)

Organ	SUVmean
Liver (n=19)	1.1 ± 0.3
Spleen (n=16)	1.4 ± 0.3
Kidney (n=20)	4.5 ± 1.5

Data are mean ± SD

A total of 42 lesions were examined on whole-body ⁶⁸Ga-DOTA-JR11 PET/CT (n=4, 3 pts; n=3, 3 pts; n=2, 7 pts; n=1, 7 pts). Liver was the most common site of disease with 30 lesions, followed by lymph nodes (n=8), bone (n=3), and lung (n=1). Lesion uptake at 60 min was variable with median SUV_max of 13 (range: 2.9-94) and SUV_peak of 10 (2.5-84) (see also Table 3). There were a wide range of tumor sizes ranging from a small vertebral lesion (1.4 ml) up to a very large lesion that encompassed almost the entire liver (1100 ml) with a median lesion volume of 15 ml. Although partial volume averaging effects inevitably lead to an underestimate of lesion uptake at small sizes, there was no statistically significant trend between lesion volume and SUV_max (r² = 0.16). A full list of lesion volumes and associated SUV_max is provided in Supplementary Table 2.

Table 3.

SUV and TNR for 42 reference lesions at 60 minutes post-administration

Site	N	SUVmax	SUVmean	SUVpeak	TNR-B	TNR-S	TNR-K	TNR-L
Lung	1	17	7.4	11	11	9	2.3	15
Liver	30	25 ± 22	11 ± 9	21 ± 19	22 ± 20	12 ± 12	6 ± 6	23 ± 23
LN	8	14 ± 20	7 ± 6	12 ± 19	10 ± 14	4 ± 3	2.3 ± 3.1	12 ± 17
Bone	3	6 ± 3	4 ± 2	5 ± 2	5 ± 3	4 ± 2	1.4 ± 0.3	6 ± 1
Total	42	21 ± 21	10 ± 8	18 ± 19	18 ± 19	10 ± 11	5 ± 6	20 ± 21

TNR: tumor-to-normal tissue (SUV_max/SUV_mean) ratio; B: blood; S: spleen; K: kidney; L: normal liver. Data are mean ± SD

In the 6 patients who had dynamic images, lesion uptake was observed to be rapid (Figs. 1 and 2), typically reaching the highest levels (SUV_max of up to 50) by 20-30 min post-injection and in most instances remaining close to plateau thereafter. Blood clearance was generally rapid but with a low-level terminal component that cleared more slowly, corresponding to a median time-zero SUV intercept of 3.7 clearing with a median biological halftime of 60 min.

Fig. 2.

Patient with atypical broncho-pulmonary NET with hepatic and osseous metastases. (a) Transverse, coronal, sagittal PET/CT image set at the level of the crosshairs shown in (b) Whole-body maximum-intensity projection images showing overall ⁶⁸Ga-DOTA-JR11 distribution. Images acquired at 62 minutes post-injection demonstrate the lack of significant normal tissue uptake, apart from kidney. Focal uptake is seen in hepatic and osseous metastases. There is significant activity (approximately 15% of the administered amount) in the urinary bladder, illustrating the primary route of excretion. (c) SUV-time curves show rapid uptake of ⁶⁸Ga-DOTA-JR11 into lesions.

Absorbed dose estimates for ⁶⁸Ga-DOTA-JR11

Normal tissue residence times for 6 patients are provided in Table 4. Those for red marrow and cardiac contents were generated from the blood activity-time curves. The full set of normal tissue absorbed dose estimates (mGy/MBq) are shown in Table 5. The highest values were (mean ± SD): urinary bladder wall (0.30 ± 0.06), kidneys (0.050 ± 0.013), liver (0.023 ± 0.014), lungs (0.021 ± 0.05), heart wall (0.020 ± 0.04), and spleen (0.018 ± 0.002). The estimated effective dose (ICRP 103) was 0.022 ± 0.003 mSv/MBq.

Table 4.

Residence times (hr) in selected organs (n = 6)

Patient	Kidney	Liver	Spleen	Lung	RM	C Cont	UB	RoB	WB
1	0.028	0.049	0.0050	0.024	0.053	0.015	0.24	0.40	0.82
2	0.017	0.032	0.0058	0.027	0.070	0.032	0.20	0.57	0.95
3	0.040	0.050	N/A	0.045	0.088	0.025	0.22	0.42	0.88
4	0.027	0.133	0.0041	0.031	0.067	0.019	0.18	0.53	1.00
5	0.030	0.048	0.0071	0.040	0.056	0.025	0.26	0.31	0.77
6	0.033	0.079	0.0071	0.053	0.078	0.035	0.20	0.45	0.93

RM: red marrow; C Cont: cardiac contents; UB: urinary bladder; RoB: remainder of body; WB: whole body; N/A: not available

Table 5.

Absorbed doses to normal tissues from ⁶⁸Ga-DOTA-JR11 (n = 6)

	Patient
Target organ	1	2	3	4	5	6	Mean ± SD
Adrenals	0.007	0.007	0.008	0.009	0.005	0.007	0.007 ± 0.002
Brain	0.004	0.005	0.005	0.006	0.003	0.004	0.004 ± 0.001
Breasts	0.005	0.005	0.005	0.006	0.003	0.004	0.005 ± 0.001
GB wall	0.007	0.007	0.007	0.010	0.005	0.007	0.007 ± 0.002
LLI wall	0.009	0.008	0.009	0.010	0.007	0.007	0.008 ± 0.001
Small intestine	0.007	0.007	0.007	0.008	0.005	0.006	0.007 ± 0.001
Stomach wall	0.006	0.006	0.006	0.008	0.004	0.005	0.006 ± 0.001
ULI wall	0.007	0.007	0.007	0.009	0.004	0.006	0.007 ± 0.001
Heart wall	0.014	0.023	0.021	0.019	0.017	0.024	0.020 ± 0.004
Kidneys	0.049	0.029	0.070	0.048	0.048	0.053	0.050 ± 0.013
Liver	0.020	0.010	0.020	0.050	0.015	0.023	0.023 ± 0.014
Lungs	0.016	0.015	0.027	0.021	0.020	0.026	0.021 ± 0.005
Muscle	0.006	0.006	0.006	0.007	0.004	0.005	0.006 ± 0.001
Ovaries	0.009	N/A	0.009	0.010	N/A	N/A	0.009 ± 0.000
Pancreas	0.006	0.007	0.007	0.009	0.005	0.006	0.007 ± 0.001
Red marrow	0.013	0.017	0.019	0.017	0.013	0.018	0.016 ± 0.003
Osteogenic cells	0.015	0.015	0.021	0.020	0.011	0.015	0.016 ± 0.004
Skin	0.004	0.005	0.005	0.006	0.003	0.004	0.004 ± 0.001
Spleen	0.018	0.017	N/A	0.016	0.020	0.020	0.018 ± 0.002
Testes	N/A	0.007	N/A	N/A	0.005	0.006	0.006 ± 0.001
Thymus	0.005	0.006	0.006	0.007	0.004	0.005	0.006 ± 0.001
Thyroid	0.005	0.005	0.005	0.006	0.003	0.004	0.005 ± 0.001
UB wall	0.378	0.230	0.343	0.289	0.297	0.237	0.30 ± 0.06
Uterus	0.013	N/A	0.013	0.013	N/A	N/A	0.013 ± 0.000
Total body	0.007	0.007	0.008	0.010	0.005	0.007	0.007 ± 0.001
Effective dose (mSv/MBq)	0.024	0.018	0.025	0.023	0.020	0.020	0.022 ± 0.003

GB: gall bladder; LLI: lower large intestine; ULI: upper large intestine; UB: urinary bladder. Effective doses were calculated using ICRP 103 weighting factors.

Data are in mGy/MBq unless otherwise specified.

DISCUSSION

This first-in-human study of ⁶⁸Ga-DOTA-JR11 demonstrated very favorable biodistribution with only minimal tracer uptake in normal parenchymal organs except for the kidneys. Tumor uptake was rapid and resulted in high-contrast images of metastatic NETs. In particular, the low background activity in liver was advantageous and facilitated detection of liver metastases. These characteristics make ⁶⁸Ga-DOTA-JR11 an attractive companion diagnostic for patient selection for therapy with ¹⁷⁷Lu-DOTA-JR11.

The reasons for differences in normal tissue uptake of ⁶⁸Ga-DOTA-JR11 and the known biodistribution of somatostatin receptor antagonists are currently not well understood. Specifically, the lack of uptake by organs with known SSTR2 expression, such as the adrenals and the pituitary gland is intriguing and requires further study. Contributory factors may include the SSTR2 antagonistic properties of ⁶⁸Ga-DOTA-JR11, the possibility of large disease “sinks” reducing agent availability and the higher peptide mass administered. It should be noted however that adrenal/pituitary uptake was not seen, even for patients with low disease burdens, while the rationale for using a higher peptide mass was for compatibility with subsequent PRRT using ¹⁷⁷Lu-DOTA-JR11, which all patients went on to have.

In a recent preclinical study, Nicolas et al. evaluated the effect of peptide mass on the biodistribution and dosimetry of ¹⁷⁷Lu-DOTA-JR11 [13]. Escalating amounts (10, 200, and 2000 pmol) did not lead to saturation of binding sites on tumor, but greatly suppressed uptake in normal SSTR2-expressing organs, thereby increasing tumor-to-background ratios.

Irrespective of its cause, the low uptake by most normal parenchymal organs resulted in favorable radiation dosimetry for ⁶⁸Ga-DOTA-JR11 when compared with published data on Gallium-labeled somatostatin receptor agonists. For example, liver and kidney doses were up to 50% lower than those reported for ⁶⁸Ga-DOTA-TOC or ⁶⁸Ga-DOTA-TATE [3, 14], while spleen dose was less by a factor of 6-15 (Table 6). Here, it should be noted that the existence of large disease sinks, especially in the liver, could lead to an underestimate of absorbed dose to normal liver, kidney and spleen as any contribution due to photon irradiation from liver disease-associated activity was not considered. The impact of this effect will vary from patient to patient, depending on the amount and biodistribution of disease and will be alleviated, to some extent, by the inclusion of the cross-dose contribution from activity in the remainder-of-body compartment.

Table 6.

Absorbed doses in selected organs using selected SSTR2 tracers

Target organ	68Ga-DOTA-JR11	68Ga-DOTA-TATE [3]	68Ga-DOTA-TATE [14]	68Ga-DOTA-TOC [14]	68Ga-NODAGA-JR11 [8]
Kidney	0.050 ± 0.013	0.092 ± 0.028	0.093 ± 0.016	0.082 ± 0.020	0.084 ± 0.031
Liver	0.023 ± 0.014	0.045 ± 0.015	0.050 ± 0.015	0.041 ± 0.014	0.022 ± 0.009
Spleen	0.018 ± 0.002	0.28 ± 0.12	0.109 ± 0.058	0.108 ± 0.065	0.06 ± 0.05
Adrenals	0.007 ± 0.002	0.015 ± 0.001	0.086 ± 0.052	0.077 ± 0.028	0.03 ± 0.01
Lungs	0.021 ± 0.005	0.012 ± 0.0004	0.006 ± 0.001	0.007 ± 0.001	0.021 ± 0.007
UB wall	0.30 ± 0.06	0.12 ± 0.06	0.098 ± 0.048	0.12 ± 0.058	0.10 ± 0.04
Red marrow	0.016 ± 0.003	0.010 ± 0.0003	0.015 ± 0.003	0.016 ± 0.003	0.011 ± 0.003
Total body	0.007 ± 0.001	0.014 ± 0.0003	0.014 ± 0.002	0.014 ± 0.002	N/A
Effective dose (mSv/MBq)	0.022 ± 0.003	0.026 ± 0.003	0.021 ± 0.003	0.021 ± 0.003	0.024 ± 0.002

Mean ± SD are provided. Data are absorbed dose in mGy/MBq unless otherwise specified.

Because of large variabilities in tumor uptake of SSTR2-targeting imaging agents, it is not straightforward to objectively compare ⁶⁸Ga-DOTA-JR11 with somatostatin receptor agonists. However, the high image contrast observed in this study with SUVmax up to 94 is certainly comparable to SUVmax reported for somatostatin receptor agonists.

Nicolas et al. [8, 9] recently reported the clinical use of ⁶⁸Ga-NODAGA-JR11 (⁶⁸Ga-OPS202) to image GEP-NETs. The use of ⁶⁸Ga-NODAGA-JR11 is supported by preclinical studies [7], which indicated that labeling DOTA-JR11 with ⁶⁸Ga reduced its SSTR2 binding affinity by a factor of approximately 80, whereas labeling NODAGA-JR11 with ⁶⁸Ga had no impact on SSTR2 binding. Interestingly, our data indicate that despite the lower affinity of ⁶⁸Ga-DOTA-JR11, substantial tumor uptake and high-contrast images are feasible. Our findings suggest that, in the range studied, receptor binding affinity may not be the key factor determining in vivo tumor uptake. The normal tissue distributions of ⁶⁸Ga-DOTA-JR11 and ⁶⁸Ga-NODAGA-JR11 were broadly similar, with somewhat higher uptake of ⁶⁸Ga-NODAGA-JR11 by kidney and around three times higher for the spleen, resulting in higher radiation doses for these organs. Additionally, despite its lower affinity, ⁶⁸Ga-DOTA-JR11 at a peptide mass dose of 80 μg (±10) had somewhat higher uptake in liver metastases (median SUV_max 18) than ⁶⁸Ga-NODAGA-JR11 (median SUV_max 10.9, 12.6 at peptide mass doses of 15 and 50 μg) and was broadly similar for all lesions combined (median SUV_max 13 for ⁶⁸Ga-DOTA-JR11 vs 12.3, 14.4 for ⁶⁸Ga-NODAGA-JR11 at 15 and 50 μg).

⁶⁸Ga-DOTA-JR11 administration was well tolerated in 18 out of 20 patients. However, two patients with functional NETs experienced symptoms with flushing, grade 3 hypotension, nausea, and lightheadedness, possibly related to the SSTR2 antagonistic properties of ⁶⁸Ga-DOTA-JR11. To our knowledge, this is in contrast to studies evaluating the safety of ⁶⁸Ga-labeled agonists such as DOTA-TATE [3], which did not report any physiologic responses to the radiopharmaceutical. Therefore, administration of ⁶⁸Ga-DOTA-JR11 by infusion may be preferable to slow bolus injection.

Conclusion

⁶⁸Ga-DOTA-JR11 is a promising companion diagnostic for selection of patients for therapy with ¹⁷⁷Lu-DOTA-JR11. The unexpected yet favorable biodistribution of ⁶⁸Ga-DOTA-JR11 requires further studies to better understand the impact of peptide mass, disease burden and SSTR2 antagonistic properties of ⁶⁸Ga-DOTA-JR11. Because of the large variability of SSTR2 expression in NETs, head-to-head comparisons in specific patient groups would likely be required to determine whether ⁶⁸Ga-DOTA-JR11 or ⁶⁸Ga-NODAGA-JR11 are preferable for detection and staging of NETs.