⁶⁸Ga-DOTA-NOC PET/CT Imaging of Neuroendocrine Tumors: Comparison with ¹¹¹In-DTPA-Octreotide (OctreoScan®)

Abstract

Purpose

Recent data have indicated that ⁶⁸Ga-DOTA-NOC positron emission tomography/X-ray computed tomography (PET/CT) may yield improved images in a shorter acquisition protocol than ¹¹¹In-DTPA-octreotide (OctreoScan®, OCT). Therefore, we performed a prospective comparison of ⁶⁸Ga-DOTA-NOC and OCT for the detection of neuroendocrine tumors (NETs).

Methods

Nineteen patients (eight carcinoid, nine pancreatic NETs, and two NE carcinoma of unknown origin) with previous positive OCT scans underwent ⁶⁸Ga-DOTA-NOC PET/CT and OCT single-photon emission computed tomography imaging for staging or follow-up. Findings were compared by region and verified with conventional imaging.

Results

All images of both modalities demonstrated focal uptake, often at multiple sites. ⁶⁸Ga-DOTA-NOC images were clearer than OCT images, facilitating interpretation. Similar foci were identified with both modalities in 41 regions, with additional foci on ⁶⁸Ga-DOTA-NOC in 21 and on OCT in 15 regions. CT, magnetic resonance imaging, or ultrasound confirmed the concordant findings in 31 of 41 regions and findings seen with ⁶⁸Ga-DOTA-NOC only in 15 of 21 regions. Findings seen with OCT only were less clear and were only confirmed in 4 of 15 regions. ⁶⁸Ga-DOTA-NOC had impact on staging in four patients and on management in three patients.

Conclusions

Although ⁶⁸Ga-DOTA-NOC and OCT images were similar, in this study, ⁶⁸Ga-DOTA-NOC demonstrated more true positive tumor foci and was better tolerated by patients. This direct comparison supports replacement of OCT with ⁶⁸Ga-DOTA-NOC-PET/CT in the evaluation of NETs.

Appendix: 68Ga-DOTA-NOC Synthesis

⁶⁸Ga-DOTA-NOC was prepared according to the procedure described by Zhernosekov et al. [22]. The radiochemical transformation was fully automated using the GE F-18 fluorination Tracerlab module with major hardware and software modifications. To the GE module, an electric Valco valve with 14 channels was added and connected to ten reagent vials and to a nitrogen gas supply valve. This electric Valco valve was connected by its exit to a three-way valve, which was further connected to a cation exchange column. The latter three-way valve was also connected via a series of valves to the ⁶⁸Ge/⁶⁸Ga generator (1,125–1,875 MBq, Obninsk Inc. Russia). The ⁶⁸Ga was eluted with 5–7 ml 0.1 N HC1 (Ultrapure). The solution was passed through the cation exchanger column (Biorad 1X8, donated by Dr. Frank Roesch, Germany). In this manner, 99% of the activity eluted from the generator was trapped by the cation exchange column. Then, the column was washed with 1 ml, 80% acetone/20% 0.15 N HCl solution for the removal of ⁶⁸Ge and other metal impurities. In the next step, 0.2 ml of the eluting solution (97.6% acetone/2.4% 0.05 N HCl) was loaded onto the column and left for 2.5 min; then, the ⁶⁸Ga was eluted from the column using an additional 0.2 ml of the same eluting solution. In this manner, approx. 90% of the activity was recovered and transferred to the reactor which contained the starting material (DOTA-NOC [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI3-Octreotide acetate salt, 50 μg, GMP grade, ABX Germany) dissolved in 7.6 ml of HEPES buffer (pH 4.1). The peptide solution was pre-heated under vacuum for 1 min at approx 30°C prior to the addition of the solution of ⁶⁸Ga, which was added drop-wise. Then, this solution was further heated to 98°C for an additional 8 min. The final pH of the reaction solution was 3.7. After cooling the solution to 30°C, the reaction mixture was loaded by nitrogen gas pressure onto RP C-18 (STRATA) column, which was further washed toward a waste vial by 5 ml of water (WFI). The pure ⁶⁸Ga-DOTA-NOC was eluted from the column using 0.4 ml ethanol and 8.5 ml saline solution. Finally, the product solution was filtered via 0.22-μm GV sterile filter and collected in the product vial. During the process, the ⁶⁸Ga activity was monitored by built-in radioactive detectors. The ⁶⁸Ge content in both the generator eluent and in the final product was periodically measured by gamma spectroscopy using HPGE detector. The ⁶⁸Ge eluted with the ⁶⁸Ga was always in accordance with the manufacturer analysis certificate, while its presence in the final product was under the detectable limit. The chemical and radiochemical purity of the final product was determined by ITLC and HPLC: Method 1: ITLC-SG 60, mobile phase 0.1 M sodium citrate, pH 5, ⁶⁸Ga-DOTA-NOC Rf = 0, free Ga-68 Rf = 0.9. Method 2: ITLC-SG 60 mobile phase 1 M ammonium acetate/methanol (1:1) ⁶⁸Ga-DOTA-NOC Rf = 0.8–1, colloid Ga Rf = 0–0.2 HPLC; C18 column 250 × 4 mm; flow rate of 1 ml/min using a gradient solution. The gradient was gradually changed during the first 20 min from initial 20% acetonitrile/80% water +0.01% TFA to 40% acetonitrile/60% water + 0.01% TFA and following the end of the procedure was reversed gradually back to the original 20% acetonitrile/80% water +0.01% TFA, ⁶⁸Ga-DOTA-NOC Rt = 18 min, and free ⁶⁸Ga Rt = 2 min. The ethanol and acetone content in the final product were determined by GC. The acetone content was <0.5% and the ethanol was <5%. The average synthesis time including the generator eluting time (n = 40) was 23 min. The average radiochemical decay-corrected yield was 54 ± 4.74%, and the non-decay-corrected yield was 70 ± 3%. Radiochemical and chemical purity were >95%.

Initially, when working with low doses of activity, not more than approximately 500 MBq, we performed the synthesis in water (WFI), with a final pH of 2.2. However, when increasing the activity level to above 500 MBq, additional radioactive peaks were detected in the HPLC with retention times between 14 and 17 min. The calculated area percentage of these labeled by-products was dependent on the starting radioactivity levels, and it ranged between 10% and 35%. When the process was done in HEPES buffer, these impurities were eliminated and the purity of the final obtained product was >95%. The nature of these labeled by-products is unclear. We assume that when working with high activity doses, degradation of the starting material ensues. It seems that the HEPES molecules have a radio-protective effect. The stability of the product was monitored by ITLC and HPLC, 2.5 h post-EOS. There was no significant change in the purity of the ⁶⁸Ga DOTA-NOC, and this permitted successful production.