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 gallium-68 labeled GRPr antagonist SB3 ( 68 Ga-SB3) has shown excellent results in (pre)clinical studies and was selected for further clinical investigation. The aims of this phase I study were to investigate 68 Ga-SB3 PET/CT-imaging of primary PCa tumors and assess safety. More aims included biodistribution, dosimetry, comparison with pathology and GRPr expression.MATERIALS AND METHODS: Ten therapy-naive, biopsy-confirmed PCa patients planned for prostatectomy were included. A 3-hour extensive PET/CT-imaging protocol was performed, within 2 weeks prior to prostatectomy. Prostate tissue was evaluated for tumor localization, Gleason Score and in vitro autoradiography was performed to determine GRPr expression. Available MRI scans performed within 3 months prior to 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 2.1 model. RESULTS: Administration of 68 Ga-SB3 (187.4 ± 40.0 MBq, 40±5 μg) was well tolerated, no significant changes in vital signs or laboratory results were observed. 68 Ga-SB3 PET/CT showed lesions in 8 out of 10 patients. Pathological analysis revealed a total of 16 tumor lesions of which PET/CT showed 14, resulting in a sensitivity of 88%. 68 Ga-SB3 PET/CT-imaging showed uptake in 2 large prostatic intraepithelial neoplasia foci, considered a precursor of 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, level of GRPr expression showed significant correlation to tracer uptake on PET/CT. Dosimetry calculations estimated the effective dose to be 0.0144 mSv/MBq, similar to other 68 Ga labeled radiopeptides. Highest absorbed dose was detected in the physiological GRPr-expressing pancreas (0.198 mGy/MBq), followed by bladder wall and kidneys. CONCLUSION: 68 Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging.

[99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes

“…The expression of gastrin releasing peptide receptors (GRPRs) in a series of human tumors has provided the rationale for the application of anti-GRPR peptide radioligands 2 of 14 in cancer diagnosis and therapy following a patient-tailored theranostic approach [1][2][3]. High levels of GRPR-expression have been indeed documented in excised patient biopsy specimens from prostate cancer (PC), especially in its early stages [4][5][6][7][8], breast cancer [9][10][11], gastrointestinal stroma tumors [12] and other human cancers [13,14]. The design of safe and effective radionuclide carriers to pathological GRPR-positive lesions was initially based on the amphibian tetradecapeptide bombesin (BBN, Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH 2 ) and its octa/nonapeptide C-terminal fragments [1,2].…”

“…During our search for clinically useful GRPR-radioantagonists, we have often employed the [ D Phe 6 ,LeuNHEt 13 ]BBN (6)(7)(8)(9)(10)(11)(12)(13) motif [27][28][29]. This potent GRPR-antagonist resulted after truncation of Met 14 and ethylamidation of Leu 13 in the [ D Phe 6 ]BBN (6)(7)(8)(9)(10)(11)(12)(13)(14) fragment [30,31].…”

“…During our search for clinically useful GRPR-radioantagonists, we have often employed the [ D Phe 6 ,LeuNHEt 13 ]BBN (6)(7)(8)(9)(10)(11)(12)(13) motif [27][28][29]. This potent GRPR-antagonist resulted after truncation of Met 14 and ethylamidation of Leu 13 in the [ D Phe 6 ]BBN (6)(7)(8)(9)(10)(11)(12)(13)(14) fragment [30,31]. Coupling of suitable chelators at the N-terminus via different linkers gave rise to a series of analogs, amenable to radiolabeling with clinically appealing radiometals.…”

“…Coupling of suitable chelators at the N-terminus via different linkers gave rise to a series of analogs, amenable to radiolabeling with clinically appealing radiometals. As a result, single photon emission computed tomography (SPECT; Tc-99m, In-111) or positron emission tomography (PET; Ga-68) diagnostic imaging and radionuclide therapy (Lu-177) could be performed [7,25,26,29,32]. Specifically, for labeling with the preeminent SPECT radiometal Tc-99m we have employed an acyclic tetraamine chelator.…”

“…The tetraamine chain positioned at the equatorial plane of an octahedron is wrapped around the trans-[ 99m Tc]Tc(O) 2 + core forming stable monocationic complexes [33]. The first such radiotracer, [ 99m Tc]Tc-DB1 (DB1, demobesin 1, [N 4 -DGA-D Phe 6 ,LeuNHEt 13 ]BBN (6)(7)(8)(9)(10)(11)(12)(13); N 4 , 6-{p-[(carboxymethoxy)-acetyl]-aminobenzyl}-1,4,8,11-tetraazaundecane); DGA, diglycolic acid), showed attractive in vivo profile in mice bearing human PC-3 xenografts [20,34]. Further development of a series of [ 99m Tc]Tc-DB1 mimics followed by structural interventions on the spacer or/and the peptide chain [35,36].…”