Novel Imaging Probes: From Design to Applications

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 12799

Special Issue Editor


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Guest Editor
Department of Chemistry, National Dong Hwa University, Hualien, Taiwan
Interests: nuclear/fluorescence imaging; peptide drug discovery; bio-orthogonal chemistry; antibiotics; tumor hypoxia

Special Issue Information

Dear Colleagues,

Molecular imaging has developed rapidly, becoming a vital tool for early clinical diagnosis, therapy monitoring, and risk stratification. Notably, achieving high-quality images heavily relies on a highly sensitive and selective imaging probe. The recent development of target-specific tracers with different imaging modalities, such as photon emission computerized tomography (SPECT), positron emission tomography (PET), and optical imaging, has experienced incredible growth. From random screening to rational design, we have seen scientists across the fields of biology, chemistry, pharmacy, and computer science develop various strategies to find probes for specific biomarkers of different diseases. Improving the pharmacokinetic characteristics of imaging probes for clinical applications is as well emphasized. On the other hand, advances in nanomaterials, radiochemistry, and new-generation fluorophores (ex. NIRF-II) have added great support to the in vivo applications of imaging probes. Furthermore, combining an imaging probe and a therapeutic drug to be a single theragnostic agent is likely a new trend that expands the application of imaging probes. In this Special Issue, “Novel Imaging Probes: From Design to Applications”, we aim to collect both original and review articles that focus on molecular imaging probe design, novel strategies of probe development, and preclinical and clinical translational studies of new imaging probes. Experts in these fields are encouraged to contribute their recent works to this Special Issue of Pharmaceuticals.

Dr. Kuo-Ting Chen
Guest Editor

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Keywords

  • molecular imaging
  • imaging probe development strategy
  • imaging probe design
  • applications of imaging probes
  • SPECT
  • PET
  • optical imaging

Published Papers (6 papers)

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Editorial

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3 pages, 196 KiB  
Editorial
Novel Imaging Probes: From Design to Applications
by Kuo-Ting Chen
Pharmaceuticals 2023, 16(10), 1506; https://doi.org/10.3390/ph16101506 - 23 Oct 2023
Viewed by 1016
Abstract
Molecular imaging has emerged as a powerful tool for clinical diagnosis [...] Full article
(This article belongs to the Special Issue Novel Imaging Probes: From Design to Applications)

Research

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18 pages, 2104 KiB  
Article
Radiochemical and Biological Evaluation of 3p-C-NETA-ePSMA-16, a Promising PSMA-Targeting Agent for Radiotheranostics
by Erika Murce, Stephen Ahenkorah, Savanne Beekman, Maryana Handula, Debra Stuurman, Corrina de Ridder, Frederik Cleeren and Yann Seimbille
Pharmaceuticals 2023, 16(6), 882; https://doi.org/10.3390/ph16060882 - 15 Jun 2023
Viewed by 1714
Abstract
Bifunctional chelators (BFCs) are a key element in the design of radiopharmaceuticals. By selecting a BFC that efficiently complexes diagnostic and therapeutic radionuclides, a theranostic pair possessing almost similar biodistribution and pharmacokinetic properties can be developed. We have previously reported 3p-C-NETA [...] Read more.
Bifunctional chelators (BFCs) are a key element in the design of radiopharmaceuticals. By selecting a BFC that efficiently complexes diagnostic and therapeutic radionuclides, a theranostic pair possessing almost similar biodistribution and pharmacokinetic properties can be developed. We have previously reported 3p-C-NETA as a promising theranostic BFC, and the encouraging preclinical outcomes obtained with [18F]AlF-3p-C-NETA-TATE led us to conjugate this chelator to a PSMA-targeting vector for imaging and treatment of prostate cancer. In this study, we synthesized 3p-C-NETA-ePSMA-16 and radiolabeled it with different diagnostic (111In, 18F) and therapeutic (177Lu, 213Bi) radionuclides. 3p-C-NETA-ePSMA-16 showed high affinity to PSMA (IC50 = 4.61 ± 1.33 nM), and [111In]In-3p-C-NETA-ePSMA-16 showed specific cell uptake (1.41 ± 0.20% ID/106 cells) in PSMA expressing LS174T cells. Specific tumor uptake of [111In]In-3p-C-NETA-ePSMA-16 was observed up to 4 h p.i. (1.62 ± 0.55% ID/g at 1 h p.i.; 0.89 ± 0.58% ID/g at 4 h p.i.) in LS174T tumor-bearing mice. Only a faint signal could be seen at 1 h p.i. in the SPECT/CT scans, whereas dynamic PET/CT scans performed after administration of [18F]AlF-3p-C-NETA-ePSMA-16 in PC3-Pip tumor xenografted mice resulted in a better tumor visualization and imaging contrast. Therapy studies with short-lived radionuclides such as 213Bi could further elucidate the therapeutic potential of 3p-C-NETA-ePSMA-16 as a radiotheranostic. Full article
(This article belongs to the Special Issue Novel Imaging Probes: From Design to Applications)
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14 pages, 3059 KiB  
Article
Synthesis and Preclinical Evaluation of Novel 68Ga-Labeled (R)-Pyrrolidin-2-yl-boronic Acid-Based PET Tracers for Fibroblast Activation Protein-Targeted Cancer Imaging
by Shreya Bendre, Hsiou-Ting Kuo, Helen Merkens, Zhengxing Zhang, Antonio A. W. L. Wong, François Bénard and Kuo-Shyan Lin
Pharmaceuticals 2023, 16(6), 798; https://doi.org/10.3390/ph16060798 - 28 May 2023
Cited by 1 | Viewed by 2262
Abstract
Fibroblast activation protein (FAP) is a membrane-tethered serine protease overexpressed in the reactive stromal fibroblasts of >90% human carcinomas, which makes it a promising target for developing radiopharmaceuticals for the imaging and therapy of carcinomas. Here, we synthesized two novel (R)-pyrrolidin-2-yl-boronic [...] Read more.
Fibroblast activation protein (FAP) is a membrane-tethered serine protease overexpressed in the reactive stromal fibroblasts of >90% human carcinomas, which makes it a promising target for developing radiopharmaceuticals for the imaging and therapy of carcinomas. Here, we synthesized two novel (R)-pyrrolidin-2-yl-boronic acid-based FAP-targeted ligands: SB02055 (DOTA-conjugated (R)-(1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)glycyl)pyrrolidin-2-yl)boronic acid) and SB04028 (DOTA-conjugated ((R)-1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)-D-alanyl)pyrrolidin-2-yl)boronic acid). natGa- and 68Ga-complexes of both ligands were evaluated in preclinical studies and compared to previously reported natGa/68Ga-complexed PNT6555. Enzymatic assays showed that FAP binding affinities (IC50) of natGa-SB02055, natGa-SB04028 and natGa-PNT6555 were 0.41 ± 0.06, 13.9 ± 1.29 and 78.1 ± 4.59 nM, respectively. PET imaging and biodistribution studies in HEK293T:hFAP tumor-bearing mice showed that while [68Ga]Ga-SB02055 presented with a nominal tumor uptake (1.08 ± 0.37 %ID/g), [68Ga]Ga-SB04028 demonstrated clear tumor visualization with ~1.5-fold higher tumor uptake (10.1 ± 0.42 %ID/g) compared to [68Ga]Ga-PNT6555 (6.38 ± 0.45 %ID/g). High accumulation in the bladder indicated renal excretion of all three tracers. [68Ga]Ga-SB04028 displayed a low background level uptake in most normal organs, and comparable to [68Ga]Ga-PNT6555. However, since its tumor uptake was considerably higher than [68Ga]Ga-PNT6555, the corresponding tumor-to-organ uptake ratios for [68Ga]Ga-SB04028 were also significantly greater than [68Ga]Ga-PNT6555. Our data demonstrate that (R)-(((quinoline-4-carbonyl)-d-alanyl)pyrrolidin-2-yl)boronic acid is a promising pharmacophore for the design of FAP-targeted radiopharmaceuticals for cancer imaging and radioligand therapy. Full article
(This article belongs to the Special Issue Novel Imaging Probes: From Design to Applications)
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15 pages, 4376 KiB  
Article
Synthesis, Fluorine-18 Radiolabeling, and In Vivo PET Imaging of a Hydrophilic Fluorosulfotetrazine
by Jason Beaufrez, Stéphane Guillouet, Yann Seimbille and Cécile Perrio
Pharmaceuticals 2023, 16(5), 636; https://doi.org/10.3390/ph16050636 - 22 Apr 2023
Cited by 2 | Viewed by 1906
Abstract
The development of 18F-fluorotetrazines, suitable for the radiolabeling of biologics such as proteins and antibodies by IEDDA ligation, represents a major challenge, especially for pre-targeting applications. The hydrophilicity of the tetrazine has clearly become a crucial parameter for the performance of in [...] Read more.
The development of 18F-fluorotetrazines, suitable for the radiolabeling of biologics such as proteins and antibodies by IEDDA ligation, represents a major challenge, especially for pre-targeting applications. The hydrophilicity of the tetrazine has clearly become a crucial parameter for the performance of in vivo chemistry. In this study, we present the design, the synthesis, the radiosynthesis, the physicochemical characterization, the in vitro and in vivo stability, as well as the pharmacokinetics and the biodistribution determined by PET imaging in healthy animals of an original hydrophilic 18F-fluorosulfotetrazine. This tetrazine was prepared and radiolabelled with fluorine-18 according to a three-step procedure, starting from propargylic butanesultone as the precursor. The propargylic sultone was converted into the corresponding propargylic fluorosulfonate by a ring-opening reaction with 18/19F-fluoride. Propargylic 18/19F-fluorosulfonate was then subject to a CuACC reaction with an azidotetrazine, followed by oxidation. The overall automated radiosynthesis afforded the 18F-fluorosulfotetrazine in 29–35% DCY, within 90–95 min. The experimental LogP and LogD7.4 values of −1.27 ± 0.02 and −1.70 ± 0.02, respectively, confirmed the hydrophilicity of the 18F-fluorosulfotetrazine. In vitro and in vivo studies displayed a total stability of the 18F-fluorosulfotetrazine without any traces of metabolization, the absence of non-specific retention in all organs, and the appropriate pharmacokinetics for pre-targeting applications. Full article
(This article belongs to the Special Issue Novel Imaging Probes: From Design to Applications)
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13 pages, 2838 KiB  
Article
Novel 68Ga-Labeled Pyridine-Based Fibroblast Activation Protein-Targeted Tracers with High Tumor-to-Background Contrast
by Arsyangela Verena, Hsiou-Ting Kuo, Helen Merkens, Jutta Zeisler, Shreya Bendre, Antonio A. W. L. Wong, François Bénard and Kuo-Shyan Lin
Pharmaceuticals 2023, 16(3), 449; https://doi.org/10.3390/ph16030449 - 16 Mar 2023
Cited by 3 | Viewed by 2675
Abstract
Compared to quinoline-based fibroblast activation protein (FAP)-targeted radiotracers, pyridine-based FAP-targeted tracers are expected to have faster pharmacokinetics due to their smaller molecular size and higher hydrophilicity, which we hypothesize would improve the tumor-to-background image contrast. We aim to develop 68Ga-labeled pyridine-based FAP-targeted [...] Read more.
Compared to quinoline-based fibroblast activation protein (FAP)-targeted radiotracers, pyridine-based FAP-targeted tracers are expected to have faster pharmacokinetics due to their smaller molecular size and higher hydrophilicity, which we hypothesize would improve the tumor-to-background image contrast. We aim to develop 68Ga-labeled pyridine-based FAP-targeted tracers for cancer imaging with positron emission tomography (PET), and compare their imaging potential with the clinically validated [68Ga]Ga-FAPI-04. Two DOTA-conjugated pyridine-based AV02053 and AV02070 were synthesized through multi-step organic synthesis. IC50(FAP) values of Ga-AV02053 and Ga-AV02070 were determined by an enzymatic assay to be 187 ± 52.0 and 17.1 ± 4.60 nM, respectively. PET imaging and biodistribution studies were conducted in HEK293T:hFAP tumor-bearing mice at 1 h post-injection. The HEK293T:hFAP tumor xenografts were clearly visualized with good contrast on PET images by [68Ga]Ga-AV02053 and [68Ga]Ga-AV02070, and both tracers were excreted mainly through the renal pathway. The tumor uptake values of [68Ga]Ga-AV02070 (7.93 ± 1.88%ID/g) and [68Ga]Ga-AV02053 (5.6 ± 1.12%ID/g) were lower than that of previously reported [68Ga]Ga-FAPI-04 (12.5 ± 2.00%ID/g). However, both [68Ga]Ga-AV02070 and [68Ga]Ga-AV02053 showed higher tumor-to-background (blood, muscle, and bone) uptake ratios than [68Ga]Ga-FAPI-04. Our data suggests that pyridine-based pharmacophores are promising for the design of FAP-targeted tracers. Future optimization on the selection of a linker will be explored to increase tumor uptake while maintaining or even further improving the high tumor-to-background contrast. Full article
(This article belongs to the Special Issue Novel Imaging Probes: From Design to Applications)
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Review

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16 pages, 3467 KiB  
Review
Nanobodies as Diagnostic and Therapeutic Tools for Cardiovascular Diseases (CVDs)
by Lorena-Andreea Bocancia-Mateescu, Dana Stan, Andreea-Cristina Mirica, Miruna Gabriela Ghita, Diana Stan and Lavinia Liliana Ruta
Pharmaceuticals 2023, 16(6), 863; https://doi.org/10.3390/ph16060863 - 9 Jun 2023
Cited by 1 | Viewed by 2480
Abstract
The aim of this review is to summarize some of the most recent work in the field of cardiovascular disease (CVD) diagnosis and therapy, focusing mainly on the role of nanobodies in the development of non-invasive imaging methods, diagnostic devices, and advanced biotechnological [...] Read more.
The aim of this review is to summarize some of the most recent work in the field of cardiovascular disease (CVD) diagnosis and therapy, focusing mainly on the role of nanobodies in the development of non-invasive imaging methods, diagnostic devices, and advanced biotechnological therapy tools. In the context of the increased number of people suffering from CVDs due to a variety of factors such as sedentariness, poor nutrition, stress, and smoking, there is an urgent need for new and improved diagnostic and therapeutic methods. Nanobodies can be easily produced in prokaryotes, lower eukaryotes, and plant and mammalian cells, and offer great advantages. In the diagnosis domain, they are mainly used as labeled probes that bind to certain surface receptors or other target molecules and give important information on the severity and extent of atherosclerotic lesions, using imaging methods such as contrast-enhanced ultrasound molecular imaging (CEUMI), positron emission tomography (PET), single-photon emission computed tomography coupled with computed tomography (SPECT/CT), and PET/CT. As therapy tools, nanobodies have been used either for transporting drug-loaded vesicles to specific targets or as inhibitors for certain enzymes and receptors, demonstrated to be involved in various CVDs. Full article
(This article belongs to the Special Issue Novel Imaging Probes: From Design to Applications)
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