Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals

Evans, Brendan; King, Andrew T; Katsifis, Andrew; Matesic, Lidia; Jamie, Joanne F.

doi:10.3390/molecules25102314

Cited by 99 publications

(83 citation statements)

References 133 publications

(233 reference statements)

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“…One potential explanation for these results might be differences in the metabolism in individual mice, which become most apparent in experiments involving small animal cohorts (e.g., n = 3 for [ 18 F, nat Ga]rhPSMA-7). Furthermore, in vivo degradation of [ 18 F, nat Ga]rhPSMA-7 isomers, especially of L-Dap-comprising compounds (7.2 and 7.4), by peptidases must be considered [28,29].…”

Section: Discussionmentioning

confidence: 99%

Preclinical comparison of four [18F, natGa]rhPSMA-7 isomers: influence of the stereoconfiguration on pharmacokinetics

et al. 2020

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Introduction Radiohybrid (rh) ligands, a novel class of prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals, can be labeled either with [18F]fluorine via isotopic exchange or with radiometals (such as [68Ga]Gallium, [177Lu]Lutetium, [225Ac]Actinium). Among these, [18F, natGa]rhPSMA-7 has recently entered clinical assessment. Aim Since [18F, natGa]rhPSMA-7 is composed of four stereoisomers ([18F, natGa]rhPSMA-7.1, -7.2, -7.3 and -7.4), we initiated a preclinical selection process to identify the isomer with the most favorable pharmacokinetics for further clinical investigation. Methods A synthetic protocol for enantiopure [19F, natGa]rhPSMA-7 isomers has been developed. The comparative evaluation of the four isomers comprised human serum albumin binding, lipophilicity, IC50, internalization and classical biodistribution studies and competition experiments in LNCaP tumor-bearing CB-17 SCID mice. In addition, a radio high-performance liquid chromatography-based method was developed allowing quantitative, intraindividual comparison of [18F, natGa]rhPSMA-7.1 to -7.4 in LNCaP tumor-bearing mice. Results Cell studies revealed high PSMA affinity and internalization for [18/19F, natGa]rhPSMA-7.2, -7.3 and -7.4, whereas [18/19F, natGa]rhPSMA-7.1 showed approximately twofold lower values. Although the biodistribution profile obtained was typical of PSMA inhibitors, it did not allow for selection of a lead candidate for clinical studies. Thus, an intraindividual comparison of all four isomers in LNCaP tumor-bearing mice was carried out by injection of a diastereomeric mixture, followed by analysis of the differential uptake and excretion pattern of each isomer. Based on its high tumor accumulation and low uptake in blood, liver and kidneys, [18F, natGa]rhPSMA-7.3 was identified as the preferred isomer and transferred into clinical studies. Conclusion [18F, natGa]rhPSMA-7.3 has been selected as a lead compound for clinical development of a [18F]rhPSMA-based candidate. The intraindividual differential uptake and excretion analysis in vivo allowed for an accurate comparison and assessment of radiopharmaceuticals.

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Section: Discussionmentioning

confidence: 99%

Preclinical comparison of four [18F, natGa]rhPSMA-7 isomers: influence of the stereoconfiguration on pharmacokinetics

et al. 2020

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“…On the other hand, a rapid enzymatic degradation by physiological peptidases is a significant limitation of peptides. Anyway, there are several strategies how to avoid this drawback including structural modifications of the C-/N-terminus, incorporation of a PEG linker or D-/unnatural AA, and cyclization [ 35 ].…”

Section: Complexes and Radiolabeling Approaches For Target-specifimentioning

confidence: 99%

Advances in Development of Radiometal Labeled Amino Acid-Based Compounds for Cancer Imaging and Diagnostics

Mikulová

Mikuš

2021

Pharmaceuticals

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Radiolabeled biomolecules targeted at tumor-specific enzymes, receptors, and transporters in cancer cells represent an intensively investigated and promising class of molecular tools for the cancer diagnosis and therapy. High specificity of such biomolecules is a prerequisite for the treatment with a lower burden to normal cells and for the effective and targeted imaging and diagnosis. Undoubtedly, early detection is a key factor in efficient dealing with many severe tumor types. This review provides an overview and critical evaluation of novel approaches in the designing of target-specific probes labeled with metal radionuclides for the diagnosis of most common death-causing cancers, published mainly within the last three years. Advances are discussed such traditional peptide radiolabeling approaches, and click and nanoparticle chemistry. The progress of radiolabeled peptide based ligands as potential radiopharmaceuticals is illustrated via novel structure and application studies, showing how the molecular modifications reflect their binding selectivity to significant onco-receptors, toxicity, and, by that, practical utilization. The most impressive outputs in categories of newly developed structures, as well as imaging and diagnosis approaches, and the most intensively studied oncological diseases in this context, are emphasized in order to show future perspectives of radiometal labeled amino acid-based compounds in nuclear medicine.

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“…The linkers by influencing the size, shape, solubility, stability, and molecular weight of the chemical structures directly support the performance of the entire radiopharmaceuticals. Moreover, the linkers affect the pharmacodynamics, affinity, and mode of excretion of the bioconjugate (Evans et al, 2020). The pharmacological behavior of radiopharmaceutical can be affected by insertion of a linking moiety as a pharmacokinetic modifier.…”

Section: Design Of Peptide-based Radiopharmaceuticals For Imaging Andmentioning

confidence: 99%

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

Cai

et al. 2020

Front. Chem.

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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.

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Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals

Cited by 99 publications

References 133 publications

Preclinical comparison of four [18F, natGa]rhPSMA-7 isomers: influence of the stereoconfiguration on pharmacokinetics

Preclinical comparison of four [18F, natGa]rhPSMA-7 isomers: influence of the stereoconfiguration on pharmacokinetics

Advances in Development of Radiometal Labeled Amino Acid-Based Compounds for Cancer Imaging and Diagnostics

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

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