Comparative evaluation of ⁶⁸Ga‐labeled NODAGA, DOTAGA, and HBED‐CC‐conjugated cNGR peptide chelates as tumor‐targeted molecular imaging probes

Abstract

The biological behavior of Ga-based radiopharmaceuticals can be significantly affected by the chelators' attributes (size, charge, lipophilicity). Thus, this study aimed at examining the influence of three different chelators, DOTAGA, NODAGA, and HBED-CC on the distribution pattern of Ga-labeled NGR peptides targeting CD13 receptors. Ga-DOTAGA-c(NGR), Ga-NODAGA-c(NGR), and Ga-HBED-CC-c(NGR) were observed to be hydrophilic with respective log p values being -3.5 ± 0.2, -3.3 ± 0.08, and -2.8 ± 0.14. The three radiotracers exhibited nearly similar uptake in human fibrosarcoma HT-1080 tumor cells with 86%, 63%, and 33% reduction during blocking studies with unlabeled cNGR peptide for Ga-DOTAGA-c(NGR), Ga-NODAGA-c(NGR), and Ga-HBED-CC-c(NGR), respectively, indicating higher receptor specificity of the first two radiotracers. The neutral radiotracer Ga-NODAGA-c(NGR) demonstrated better target-to-non-target ratios during in vivo studies compared to its negatively charged counterparts, Ga-DOTAGA-c(NGR) and Ga-HBED-CC-c(NGR). The three radiotracers had similar HT-1080 tumor uptake and being hydrophilic exhibited renal excretion with minimal uptake in non-target organs. Significant reduction (p< .005) in HT-1080 tumor uptake of the radiotracers was observed during blocking studies. It may be inferred from these studies that the three radiotracers are promising probes for in vivo imaging of CD13 receptor expressing cancer sites; however, Ga-NODAGA-c(NGR) is a better candidate.

Molecular Imaging of Aminopeptidase N in Cancer and Angiogenesis

“…For PET imaging, three different 68 Ga chelators conjugated to a cCNGRC targeting unit were compared. The uncharged NODAGA chelator outperformed DOTAGA and HBED and exhibited higher target to nontarget specificity [ 56 ]. A radiolabeled peptide drug conjugate was also created as a theranostic approach for imaging and targeted chemotherapy of melanoma.…”

68Ga‐labeling of internalizing RGD (iRGD) peptide functionalized with DOTAGA and NODAGA chelators

“…The chelator DOTAGA leads to a negatively charged 68 Ga‐complex, whereas 68 Ga‐NODAGA chelate is neutral . However, DOTAGA has an edge over NODAGA as it forms stable complexes with therapeutic radionuclides ( 90 Y/ 177 Lu) and thus can be translated for preparation of therapeutic radiopharmaceuticals . The two radiotracers, 68 Ga‐DOTAGA‐iRGD ( 68 Ga‐DiRGD) and 68 Ga‐NODAGA‐iRGD ( 68 Ga‐NiRGD), were analyzed for the radiochemical yield/purity and partition coefficient.…”

Design, synthesis, and comparative evaluation of 99mTc(CO)3‐labeled N‐terminal and C‐terminal modified asparagine–glycine–arginine peptide constructs

“…The CD13 receptors specifically recognize asparagine–glycine–arginine (NGR) motif containing peptides . Radiometalated NGR peptide constructs are hence being explored as molecular imaging probes for detection and monitoring of CD13 receptor‐expressing malignant sites . According to a literature report, carboxyl terminal of cyclic NGR [cCNGRC] peptide is a favorable position for tagging radioisotopes/drugs rather than N‐terminal that plays more important role in receptor binding .…”

“…Radiometalation of NGR peptides has been reported with 64 Cu, 68 Ga, and 99m Tc for diagnostic purpose . However, single‐photon emission computed tomography (SPECT) radioisotope, 99m Tc has wider coverage in nuclear medicine hospitals because of lower infrastructure and financial requirement in comparison with positron emission tomography (PET) isotopes, 64 Cu and 68 Ga .…”

“…15,23 Radiometalation of NGR peptides has been reported with 64 Cu, 68 Ga, and 99m Tc for diagnostic purpose. [7][8][9][10][11][12] However, single-photon emission computed tomography (SPECT) radioisotope, 99m Tc has wider coverage in nuclear medicine hospitals because of lower infrastructure and financial requirement in comparison with positron emission tomography (PET) isotopes, 64 Cu and 68 Ga. 24,25 The nuclear (E γ = 140 keV, 89%) and physical (t ½ = 6 h) properties of 99m Tc are ideally suited for carrying out labeling and imaging procedures. The diverse redox chemistry of 99m Tc offers ample options of oxidation states and metal cores to choose for peptide labeling.…”