Design, Synthesis, Radiolabeling, and Biologic Evaluation of Three ¹⁸F-FDG-Radiolabeled Targeting Peptides for the Imaging of Apoptosis

Abstract

Background: Early detection of apoptosis is very important for therapy and follow-up treatment in various pathologic conditions. Annexin V interacts strongly and specifically with phosphatidylserine, specific biomarkers of apoptosis with some limitations. Small peptides are suitable alternatives to annexin V. A reliable and noninvasive in vivo technique for the detection of apoptosis is in great demand. Based on our previous studies, three new peptide analogs of LIKKPF (Leu-Ile-Lys-Lys-Pro-Phe) as apoptosis imaging agents were developed. Materials and Methods: Aoa-LIKKP-Cl-F, Aoe-LIKKP-Pyr-F, and Aoe-LIKKP-Nap-F were synthesized, functionalized with aminooxy, and radiolabeled with 18 F-FDG. Their biologic properties were evaluated in vitro using apoptotic Jurkat cells. 18 F-FDG-Aoe-LIKKP-Pyr-F peptide was injected into normal and apoptotic mice models for biodistribution and in vivo positron emission tomography/computed tomography imaging studies. Results: 18 F-FDG-Aoe-LIKKP-Pyr-F peptide showed higher affinity for apoptotic cells. The localization of peptide in apoptotic liver mice was confirmed in biodistribution and imaging studies. Conclusion: The results showed that Aoe-LIKKP-Pyr-F peptide is an auspicious agent for molecular imaging of apoptosis.

Apoptosis Imaging in Oncology by Means of Positron Emission Tomography: A Review

“…However, the radiolabelled version proved to be significantly less potent to interact with PS when compared to Annexin V (IC50 value in the low mM range versus nM range) and their in vivo stability proved to be very poor. LIPKFF was also labelled with 18 F through the bioconjugation chemistry with FDG but the resulting radiolabelled peptide did not allow for adequate imaging of PS-expression on apoptotic tumour cells [31]. Ben Azzouna et al radiolabelled PGDLSR with 68 Ga via the conjugation of beta-alanine-NODAGA to the N-terminus [32].…”

Peptide Multimerization as Leads for Therapeutic Development

“…The deployment of a peptide attached to a radio-nuclide has been the focus of a great deal of research to image specific peptide receptors and targeted activity towards receptors overexpressed on tumors over the last two decades [172]. For example, Khoshbakht et al developed a 18 F-FDG-Aoe-LIKKP-Pyr-F peptide with higher affinity for apoptotic cells and further hypothesised its potential in the diagnosis and therapy monitoring of apoptosisrelated pathologies [173]. Aweda et al [174] used a polycationic peptide conjugated with positron emission tomography (PET) probes, namely 1, 4, 7, 10-tetraazacyclododecane-N ,N ,N ,N-tetraacetic acid (DOTA) and AB1-HLys-DOTA, to target bacterial membrane lipids.…”

Radionuclide imaging of apoptosis for clinical application

“…Appearing early at the apoptosis cascade, this disturbed asymmetry can be served as a potential biomarker for radionuclide imaging of apoptosis due to the broad expression and easy accessibility of PE/PS [ 5 ]. Nowadays, a rich assortment of imaging probes targeting the externalized anionic phospholipids, such as Annexin V [ 11 ], synaptotagmin I derivatives [ 12 ], lactadherin [ 13 ], PS-binding peptides [ 14 ] and monoclonal antibody fragments [ 15 ], Zn-DPA complexes [ 16 ], as well as duramycin [ 17 ], have been developed for distinguishing of apoptotic cells.…”