Strategies for improving stability and pharmacokinetic characteristics of radiolabeled peptides for imaging and therapy

Gharibkandi, Nasrin Abbasi; Conlon, J. Michael; Hosseinimehr, Seyed Jalal

doi:10.1016/j.peptides.2020.170385

Cited by 32 publications

(33 citation statements)

References 99 publications

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“…For this purpose, 29 was first reacted with the c(RGDfK) derivatives 10-15, which produced the monovalent intermediates 30-35. These were further reacted with the GG-Nle-(DHfRWK) derivatives 16-21 into the final products 1-6 (Scheme 5), as this order gave better results (in terms of achievable isolated yields) than did first conjugating the structurally more demanding peptides 16-21 followed by the smaller ones (10)(11)(12)(13)(14)(15). The conjugation of the peptide-linker conjugates 10-13 and 16-19 was conducted analogously to the synthesis of the peptide-linker conjugates by directly reacting the starting materials in DMF using DIPEA as a base.…”

Section: Synthesis Of the Heterobivalent Sifalin-modified Peptidic Ligandsmentioning

confidence: 99%

“…Their pharmacokinetics prove to be very advantageous due to rapid tissue penetration, target accumulation and elimination from non-target tissues [9,10]. Therefore, numerous radiolabeled peptides have been developed for both the diagnosis and therapy of malignancies over the last decades [11,12].…”

Section: Introductionmentioning

confidence: 99%

“…So far, the concept to develop an HBPL based on an MC1R-specific peptide ([Cys 3,4,10 , DPhe 7 , Arg 11 ]αMSH [3][4][5][6][7][8][9][10][11][12][13] ) and an integrin α v β 3 -affine peptide (c(RGDyD) (cyclic Arg-Gly-Asp-DTyr-Asp)) has only been described once for the radiotracer 99m Tc-RGD-Lys-(Arg 11 )CCMSH intended for tumor therapy driven by caspase-3-induced apoptosis induction [31]. The evaluation of this compound was performed in vitro on MC1R-exhibiting B16F1 cells and in vivo in B16F1 melanoma-bearing mice.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin αvβ3 and the MC1 Receptor—Suitable for the Specific Visualization of Melanomas?

et al. 2021

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Combining two peptides addressing two different receptors to a heterobivalent peptidic ligand (HBPL) is thought to enable an improved tumor-targeting sensitivity and thus tumor visualization, compared to monovalent peptide ligands. In the case of melanoma, the Melanocortin-1 receptor (MC1R), which is stably overexpressed in the majority of primary malignant melanomas, and integrin αvβ3, which is involved in lymph node metastasis and therefore has an important role in the transition from local to metastatic disease, are important target receptors. Thus, if a radiolabeled HBPL could be developed that was able to bind to both receptor types, the early diagnosis and correct staging of the disease would be significantly increased. Here, we report on the design, synthesis, radiolabeling and in vitro and in vivo testing of different SiFAlin-modified HBPLs (SiFA = silicon fluoride acceptor), consisting of an MC1R-targeting (GG-Nle-c(DHfRWK)) and an integrin αvβ3-affine peptide (c(RGDfK)), being connected by a symmetrically branching framework including linkers of differing length and composition. Kit-like 18F-radiolabeling of the HBPLs 1–6 provided the labeled products [18F]1–[18F]6 in radiochemical yields of 27–50%, radiochemical purities of ≥95% and non-optimized molar activities of 17–51 GBq/µmol within short preparation times of 25 min. Besides the evaluation of radiotracers regarding logD(7.4) and stability in human serum, the receptor affinities of the HBPLs were investigated in vitro on cell lines overexpressing integrin αvβ3 (U87MG cells) or the MC1R (B16F10). Based on these results, the most promising compounds [18F]2, showing the highest affinity to both target receptors (IC50 (B16F10) = 0.99 ± 0.11 nM, IC50 (U87MG) = 1300 ± 288 nM), and [18F]4, exhibiting the highest hydrophilicity (logD(7.4) = −1.39 ± 0.03), were further investigated in vivo and ex vivo in a xenograft mouse model bearing both tumors. For both HBPLs, clear visualization of B16F10, as well as U87MG tumors, was feasible. Blocking studies using the respective monospecific peptides demonstrated both peptide binders of the HBPLs contributing to tumor uptake. Despite the somewhat lower target receptor affinities (IC50 (B16F10) = 6.00 ± 0.47 nM and IC50 (U87MG) = 2034 ± 323 nM) of [18F]4, the tracer showed higher absolute tumor uptakes ([18F]4: 2.58 ± 0.86% ID/g in B16F10 tumors and 3.92 ± 1.31% ID/g in U87MG tumors; [18F]2: 2.32 ± 0.49% ID/g in B16F10 tumors and 2.33 ± 0.46% ID/g in U87MG tumors) as well as higher tumor-to-background ratios than [18F]2. Thus, [18F]4 demonstrates to be a highly potent radiotracer for the sensitive and bispecific imaging of malignant melanoma by PET/CT imaging and impressively illustrates the suitability of the underlying concept to develop heterobivalent integrin αvβ3- and MC1R-bispecific radioligands for the sensitive and specific imaging of malignant melanoma by PET/CT.

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Section: Synthesis Of the Heterobivalent Sifalin-modified Peptidic Ligandsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin αvβ3 and the MC1 Receptor—Suitable for the Specific Visualization of Melanomas?

et al. 2021

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“…The pharmacological behavior of radiopharmaceutical can be affected by insertion of a linking moiety as a pharmacokinetic modifier. Insertion of amino acid or aliphatic linkers between the two usually does not significantly reduce receptor binding affinity (Abbasi Gharibkandi et al, 2020). For one thing, the shorter, more polarizable linkers tend to render a more hydrophilic radioligand with primary excretion via the renalurinary pathway, for another long-chained aliphatic linkers tend to produce more hydrophobic radiopeptides with unfavorably slow clearance via the hepatobiliary pathway.…”

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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“…Peptides usually show high selectivity for tumor cells, rapid tumor tissue penetration, and rapid clearance from non-target tissues and circulation. However, the moderate tumor uptake because of the short retention time frequently causes problem in the case of peptide probes, which contain small molecular weight peptides [9]. In addition to the applied vector molecule and chelator, the chemical structure of the linker unit also has a significant effect on the binding affinity, pharmacokinetics, and biodistribution of radiometal-based radiopharmaceuticals [10].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel, Dual-Targeting 68Ga-NODAGA-LacN-E[c(RGDfK)]2 Glycopeptide as a PET Imaging Agent for Cancer Diagnosis

et al. 2021

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Radiolabeled peptides possessing an Arg-Gly-Asp (RGD) motif are widely used radiopharmaceuticals for PET imaging of tumor angiogenesis due to their high affinity and selectivity to αvβ3 integrin. This receptor is overexpressed in tumor and tumor endothelial cells in the case of numerous cancer cell lines, therefore, it is an excellent biomarker for cancer diagnosis. The galectin-3 protein is also highly expressed in tumor cells and N-acetyllactosamine is a well-established ligand of this receptor. We have developed a synthetic method to prepare a lactosamine-containing radiotracer, namely 68Ga-NODAGA-LacN-E[c(RGDfK)]2, for cancer diagnosis. First, a lactosamine derivative with azido-propyl aglycone was synthetized. Then, NODAGA-NHS was attached to the amino group of this lactosamine derivative. The obtained compound was conjugated to an E[c(RGDfK)]2 peptide with a strain-promoted click reaction. We have accomplished the radiolabeling of the synthetized NODAGA-LacN-E[c(RGDfK)]2 precursor with a positron-emitting 68Ga isotope (radiochemical yield of >95%). The purification of the labeled compound with solid-phase extraction resulted in a radiochemical purity of >99%. Subsequently, the octanol–water partition coefficient (log P) of the labeled complex was determined to be −2.58. In addition, the in vitro stability of 68Ga-NODAGA-LacN-E[c(RGDfK)]2 was investigated and it was found that it was stable under the examined conditions.

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Strategies for improving stability and pharmacokinetic characteristics of radiolabeled peptides for imaging and therapy

Cited by 32 publications

References 99 publications

Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin αvβ3 and the MC1 Receptor—Suitable for the Specific Visualization of Melanomas?

Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin αvβ3 and the MC1 Receptor—Suitable for the Specific Visualization of Melanomas?

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

Synthesis of Novel, Dual-Targeting 68Ga-NODAGA-LacN-E[c(RGDfK)]2 Glycopeptide as a PET Imaging Agent for Cancer Diagnosis

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