GRPr Antagonist 68Ga-SB3 PET/CT Imaging of Primary Prostate Cancer in Therapy-Naïve Patients

Abstract

The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer (PCa) cells, making it an excellent tool for targeted imaging. The ⁶⁸Ga-labeled GRPr antagonist SB3 has shown excellent results in preclinical and clinical studies and was selected for further clinical investigation. The aims of this phase I study were to investigate ⁶⁸Ga-SB3 PET/CT imaging of primary PCa tumors and assess safety. More aims included an investigation of biodistribution and dosimetry and a comparison with pathology and GRPr expression. Methods: Ten therapy-naïve, biopsy-confirmed PCa patients planned for prostatectomy were included. A 3-h extensive PET/CT imaging protocol was performed within 2 wk before prostatectomy. Prostate tissue was evaluated for tumor localization and Gleason score, and in vitro autoradiography was performed to determine GRPr expression. Available MRI scans performed within 3 mo before the study were matched. For dosimetry, residence times were estimated and effective dose to the body as well as absorbed doses to organs were calculated using the IDAC dose model, version 2.1. Results: Administration of ⁶⁸Ga-SB3 (187.4 ± 40.0 MBq, 40 ± 5 μg) was well tolerated; no significant changes in vital signs or laboratory results were observed. ⁶⁸Ga-SB3 PET/CT showed lesions in 8 of 10 patients. Pathologic analysis revealed a total of 16 tumor lesions, of which PET/CT showed 14, resulting in a sensitivity of 88%. ⁶⁸Ga-SB3 PET/CT imaging showed uptake in 2 large prostatic intraepithelial neoplasia foci, considered a precursor to PCa, resulting in an 88% specificity. Autoradiography of tumor lesions revealed heterogeneous GRPr expression and was negative in 4 patients. Both PET/CT-negative patients had a GRPr-negative tumor. In autoradiography-positive tumors, the level of GRPr expression showed a significant correlation to tracer uptake on PET/CT. Dosimetry calculations estimated the effective dose to be 0.0144 mSv/MBq, similar to other ⁶⁸Ga-labeled radiopeptides. The highest absorbed dose was detected in the physiologic GRPr-expressing pancreas (0.198 mGy/MBq), followed by the bladder wall and kidneys. Conclusion:⁶⁸Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging.

Keywords: PET/CT; gastrin-releasing peptide receptor; prostate cancer; tumor imaging.

Graphical abstract

FIGURE 1.

Schematic representation of research protocol. (A) Protocol consisting of CT scans (gray), dynamic scan (red), static images (green), and whole-body scans (blue). (B) Tissue was cut into 4-mm sections; 1 section was fresh-frozen, and remainder were formalin-fixed and paraffin-embedded. Slides were stained with hematoxylin and eosin and evaluated by pathologist. Autoradiography was performed on slides of frozen sections. abd = abdomen; AR = autoradiography; H&E = hematoxylin and eosin.

FIGURE 2.

⁶⁸Ga-SB3 PET/CT imaging of large tumor (GS 3 + 4 = 7) in primary-PCa patient. (A) Maximum-intensity projection 60 min after injection. (B) PET (top) and PET/CT (bottom) imaging 60 min after injection; tumor SUV_max, 22.7. (C) PET imaging 210 min after injection; tumor SUV_max, 20.0. (E) Corresponding histopathologic slides with tumor delineated in red.

FIGURE 3.

⁶⁸Ga-SB3 PET/CT imaging of primary PCa patient. Very small tumor (GS 3 + 3 = 6; orange arrows) was not detected in biopsies; however, there was elevated prostate-specific antigen and family history of PCa. Catheter is indicated by yellow arrow. (A) Maximum-intensity projection 60 min after injection. (B) PET (top) and PET/CT (bottom) imaging 60 min after injection; tumor SUV_max, 4.4. (C) At 210 min after injection, with catheter removed before scan; tumor SUV_max, 4.3. (D) Corresponding histopathologic slides with tumor delineated in red.

FIGURE 4.

Biodistribution of physiologic uptake and tumor uptake of ⁶⁸Ga-SB3 60 min after injection in therapy-naïve PCa patients. Mean SUV_max and SUV_mean are depicted with SD. LES = lower esophageal sphincter; ASC = anal sphincter complex.

FIGURE 5.

Imaging of PCa and high-grade PIN in PCa patient. (Left) SUV PET image 60 min after injection, showing almost equal uptake in PCa and PIN. (Right) Corresponding histopathology slide, with tumor and PIN delineated in red and yellow, respectively.

FIGURE 6.

Pharmacokinetic excretion patterns of ⁶⁸Ga-SB3 from pancreas, tumor, and normal prostate. Pancreas and prostate show excretion with biologic half-time of 196 and 135 min, respectively. Excretion phase of tumor shows half-time of 235 min. Fits (solid lines) and 95% CIs (dotted lines) are indicated.