New Frontiers in Molecular Imaging Using Peptide-Based Radiopharmaceuticals for Prostate Cancer

Abstract

The high incidence of prostate cancer (PCa) increases the need for progress in its diagnosis, staging, and precise treatment. The overexpression of tumor-specific receptors for peptides in human cancer cells, such as gastrin-releasing peptide receptor, natriuretic peptide receptor, and somatostatin receptor, has indicated the ideal molecular basis for targeted imaging and therapy. Targeting these receptors using radiolabeled peptides and analogs have been an essential topic on the current forefront of PCa studies. Radiolabeled peptides have been used to target receptors for molecular imaging in human PCa with high affinity and specificity. The radiolabeled peptides enable optimal quick elimination from blood and normal tissues, producing high contrast for positron emission computed tomography and single-photon emission computed tomography imaging with high tumor-to-normal tissue uptake ratios. Owing to their successful application in visualization, peptide derivatives with therapeutic radionuclides for peptide receptor radionuclide therapy in PCa have been explored in recent years. These developments offer the promise of personalized, molecular medicine for individual patients. Hence, we review the preclinical and clinical literature in the past 20 years and focus on the newer developments of peptide-based radiopharmaceuticals for the imaging and therapy of PCa.

[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.…”

“…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].…”

“…In the present study, we decided to explore the effect of Gly 11 by Sar 11 (sarcosine, N-methylglycine) substitution on the profile of a new [ 99m Tc]Tc-DB1 mimic, [ 99m Tc]Tc-DB15 ([ 99m Tc]Tc-N 4 -AMA-DGA-D Phe 6 ,Sar 11 ,LeuNHEt 13 ]BBN (6)(7)(8)(9)(10)(11)(12)(13); N 4 : 6-carboxy-1,4,8,11tetraazaundecane, AMA: p-aminomethyl(aniline); Figure 1). Previous studies have shown that replacement of Gly 11 by DAla 11 resulted in radioligands of higher metabolic stability, but without notable improvement of end-pharmacokinetics [35,37].…”