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Special Issue "Novel Imaging Probes: From Design to Applications"

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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 5652

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Dr. Kuo-Ting Chen

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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 (5 papers)

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Research

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Open AccessArticle

Radiochemical and Biological Evaluation of 3p-C-NETA-ePSMA-16, a Promising PSMA-Targeting Agent for Radiotheranostics

and

Pharmaceuticals 2023, 16(6), 882; https://doi.org/10.3390/ph16060882 - 15 Jun 2023

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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 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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Open AccessArticle

Synthesis and Preclinical Evaluation of Novel ⁶⁸Ga-Labeled (R)-Pyrrolidin-2-yl-boronic Acid-Based PET Tracers for Fibroblast Activation Protein-Targeted Cancer Imaging

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

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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 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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Open AccessArticle

Synthesis, Fluorine-18 Radiolabeling, and In Vivo PET Imaging of a Hydrophilic Fluorosulfotetrazine

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Pharmaceuticals 2023, 16(5), 636; https://doi.org/10.3390/ph16050636 - 22 Apr 2023

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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 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 LogD_7.4 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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Open AccessArticle

Novel ⁶⁸Ga-Labeled Pyridine-Based Fibroblast Activation Protein-Targeted Tracers with High Tumor-to-Background Contrast

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 1 | Viewed by 1388

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 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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Open AccessReview

Nanobodies as Diagnostic and Therapeutic Tools for Cardiovascular Diseases (CVDs)

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 - 09 Jun 2023

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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 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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