Clinical Translation of Gastrin Releasing Peptide Receptor Antagonist ⁶⁸Ga-NOTA-RM26 in Healthy Volunteers and Prostate Cancer Patients

Objectives: This study was designed to study the safety, biodistribution, radiation dosimetry of gastrin-releasing peptide receptor (GRPR) targeting PET tracer ⁶⁸Ga-NOTA-RM26, and to assess the clinical diagnostic value based on GRPR antagonist in patients with prostate cancer. GRPR agonist ⁶⁸Ga-NOTA-Aca-BBN(7-14) was used for direct comparison.

Methods: A macrocyclic chelator, 1,4,7-triazacyclononane-N,N’,N”-triacetic acid (NOTA) conjugated GRPR antagonist RM26 was synthesized and labeled with ⁶⁸Ga. After the study protocol was approved by the Institute Review Board, five healthy volunteers (M 3, F 2, age range 32-54 y) were enrolled to validate the safety of ⁶⁸Ga-NOTA-RM26. A total of fifteen patients (age range, 57-79 y, mean age, 68.0 ± 6.7 y), with newly diagnosed prostate cancer by sextant core needle biopsy and without any prior therapy, were recruited with written informed consent. For the healthy volunteers, after low-dose CT scan, 111-148 MBq (3-4 mCi) of ⁶⁸Ga-NOTA-RM26 was injected intravenously, followed by serial whole-body PET acquisitions. The acquisition duration was 40 sec/bed position for the 5, 10 and 15 min time points, 2 min/bed position for the 30, 45 and 60 min time points. Dosimetry was calculated using the OLINDA/EXM software. All the patients underwent PET/CT scans at 30 min and 90 min after intravenous injection of 1.85 MBq (0.05 mCi) per kilogram body weight of ⁶⁸Ga-NOTA-RM26, and 9 patients also accepted ⁶⁸Ga-NOTA-BBN(7-14) PET/CT for comparison within 1 week. GRPR immunohistochemical staining of tumor samples against GRPR was performed and correlated with PET.

Results: The whole labeling process of ⁶⁸Ga-NOTA-RM26 took about 30 min with a radiochemical purity of greater than 95%. The administration of ⁶⁸Ga-NOTA-RM26 was well tolerated by all subjects with no adverse symptoms being noticed or reported during the whole procedure and 2 weeks follow up. A patient would be exposed to a radiation dose of 2.70 mSv with an injected dose of 129.5 MBq (3.5 mCi). The tracer showed the highest accumulation in the pancreas with a SUVmean of 20.34 ± 2.54 at 30 min post injection (p.i.) due to the high level expression of GRPR. The stomach wall, spleen and liver showed moderate uptake with SUVs of 1.32 ± 0.39, 1.28 ± 0.24 and 1.27 ± 0.20 at 30 min p.i., respectively. Uptakes in the skeletal system, muscle, brain, lungs were quite low. For the fifteen patients with newly diagnosed prostate cancer, ⁶⁸Ga-NOTA-RM26 PET/CT showed positive findings in eleven patients, with tracer strongly localized in primary prostate-confined lesions (SUVmax 3.7~10.9, mean ± SD 7.20 ± 2.06), and also detected 19 metastatic lymph nodes in three patients with SUVmax (2.3~9.2, mean ± SD 4.98 ± 2.15) and 21 bone metastasis lesions in four patients with SUVmax (1.9~13.7, mean ± SD 5.91 ± 4.52), respectively. Nine patients also underwent ⁶⁸Ga-NOTA-BBN(7-14) PET/CT, in which only 5 primary tumors, 7 lymph nodes and 9 bone lesions were positive with the SUVmax of 2.71 ± 1.31, 3.05 ± 1.70, and 4.91 ± 3.85, respectively. The immunohistochemical staining result showed positive GRPR expression in 13/17 samples from primary tumor from needle biopsy or postoperative samples. There was significant positive correlation between SUV from ⁶⁸Ga-NOTA-RM26 PET and expression level of GRPR (P < 0.001). Among them, 2 patients presented positive ⁶⁸Ga-NOTA-RM26 but negative ⁶⁸Ga-NOTA-BBN(7-14) PET were confirmed to have moderate GRPR expression from immunohistochemical staining of the biopsy samples.

Conclusion: This study indicates the safety and significant efficiency of GRPR antagonist ⁶⁸Ga-NOTA-RM26. ⁶⁸Ga-NOTA-RM26 PET/CT would have remarkable value in detecting both primary prostate cancer and metastasis. ⁶⁸Ga-NOTA-RM26 is also expected to be superior to GRPR agonist as an imaging marker to evaluate GRPR expression in prostate cancer. Research Support: Intramural Research Program (IRP) of NIBIB, NIH $$graphic_B8B6D2DE-C7B2-4824-962D-C05F8F5DDF94$$