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

Simple Summary: Radiolabeled gastrin-releasing peptide receptor (GRPR)-antagonists have been proposed for diagnostic imaging and radionuclide therapy-theranostics-of human tumors, including prostate (PC) and breast cancer (BC). We herein present [Tc-99m]Tc-DB15, a SPECT radiotracer based on the potent GRPR-antagonist [(D)Phe(6),LeuNHEt(13)]BBN(6-13). After Sar(11)/Gly(11)-replacement an acyclic tetraamine was coupled at the N-terminus via a spacer allowing for stable binding of the diagnostic radiometal Tc-99m. The forming [Tc-99m]Tc-DB15 radiotracer displayed high in vitro uptake in GRPR-expressing mammary (T-47D) and prostate cancer (PC-3) cells. Furthermore, it showed an attractive biodistribution profile in mice bearing T-47D or PC-3 xenografts. A pilot proof-of-principle study of [Tc-99m]Tc-DB15 in PC and BC patients applying SPECT is currently under way. Promising results from the first two BC patients are presented herein. Diagnostic imaging and radionuclide therapy of prostate (PC) and breast cancer (BC) using radiolabeled gastrin-releasing peptide receptor (GRPR)-antagonists represents a promising approach. We herein propose the GRPR-antagonist based radiotracer [Tc-99m]Tc-DB15 ([Tc-99m]Tc-N-4-AMA-DGA-(D)Phe(6),Sar(11),LeuNHEt(13)]BBN(6-13); N-4: 6-carboxy-1,4,8,11-tetraazaundecane, AMA: aminomethyl-aniline, DGA: diglycolic acid) as a new diagnostic tool for GRPR-positive tumors applying SPECT/CT. The uptake of [Tc-99m]Tc-DB15 was tested in vitro in mammary (T-47D) and prostate cancer (PC-3) cells and in vivo in T-47D or PC-3 xenograft-bearing mice as well as in BC patients. DB15 showed high GRPR-affinity (IC50 = 0.37 +/- 0.03 nM) and [Tc-99m]Tc-DB15 strongly bound to the cell-membrane of T-47D and PC-3 cells, according to a radiolabeled antagonist profile. In mice, the radiotracer showed high and prolonged GRPR-specific uptake in PC-3 (e.g., 25.56 +/- 2.78 %IA/g vs. 0.72 +/- 0.12 %IA/g in block; 4 h pi) and T-47D (e.g., 15.82 +/- 3.20 %IA/g vs. 3.82 +/- 0.30 %IA/g in block; 4 h pi) tumors, while rapidly clearing from background. In patients with advanced BC, the tracer could reveal several bone and soft tissue metastases on SPECT/CT. The attractive pharmacokinetic profile of [Tc-99m]DB15 in mice and its capability to target GRPR-positive BC lesions in patients highlight its prospects for a broader clinical use, an option currently being explored by ongoing clinical studies.