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Recent Trends in PET/CT Tracer Development and Multimodal Imaging

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 13286

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Special Issue Editors

Prof. Dr. Olaf Prante

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Guest Editor

Department of Nuclear Medicine, Translational Research Center, Molecular Imaging and Radiochemistry, Friedrich-Alexander University (FAU), 91054 Erlangen, Germany
Interests: positron emission tomography; fluorine-18; glycoconjugates; subtype selective PET ligands; neurotensin receptor; pancreatic tumors; endoradiotherapy; small animal imaging; translation into clinics

Prof. Dr. Tobias Bäuerle

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Guest Editor

Department of Radiology and Preclinical Imaging Platform Erlangen, Friedrich-Alexander University (FAU), 91054 Erlangen, Germany
Interests: multimodal imaging; radiomics; biomarker; bone metastases; treatment response

Special Issue Information

Dear Colleagues,

In the field of research on the development of new radiochemistry methods, innovative radiotracers and imaging agents for PET/CT studies and in vivo optical imaging, including multifunctional imaging agents, there has been major progress during the past decade. Especially in terms of chemoselectivity and labeling efficacy, the availability of imaging agents for preclinical (multimodal) imaging studies has enormously increased. In the field of PET chemistry, a large variety of validated labeling methods and upcoming new positron emitters, such as Zr-89, offer an even more simplified strategy for translation of innovative radiopharmaceuticals into the clinics. Similarly, new imaging agents for in vivo use are valuable tools and interesting efforts have been made, to develop molecules that could be applied to imaging-guided therapy of various types of cancer. These approaches accelerate the pronounced use of PET/CT and multimodal imaging in preclinical studies and even clinical trials.

We invite young scientists and principle investigators to contribute original research articles as well as review articles that present modern techniques in PET/CT tracer development, such as multifunctional tracers, and related disciplines concerned with preclinical multimodal imaging in the field of MR, ultrasound, CT or SPECT. Studies should focus on monitoring therapy of various cancer types and thus facilitating translational research.

We are interested in original as well as review articles that represent the current role of imaging agent development and multimodal imaging of cancers in facilitating translation into the clinics.

Prof. Dr. Olaf Prante
Prof. Dr. Tobias Bäuerle
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

tracer development
multimodel imaging
multifunctional imaging agents
small animal PET
CT
SPECT
MR
ultrasound
fluorescence
treatment response
translational research

Published Papers (6 papers)

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Research

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30 pages, 3950 KiB

Open AccessArticle

Development of a Neurotensin-Derived ⁶⁸Ga-Labeled PET Ligand with High In Vivo Stability for Imaging of NTS₁ Receptor-Expressing Tumors

by Lisa Schindler, Jutta Moosbauer, Daniel Schmidt, Thilo Spruss, Lukas Grätz, Steffen Lüdeke, Frank Hofheinz, Sebastian Meister, Bernd Echtenacher, Günther Bernhardt, Jens Pietzsch, Dirk Hellwig and Max Keller

Cancers 2022, 14(19), 4922; https://doi.org/10.3390/cancers14194922 - 8 Oct 2022

Cited by 4 | Viewed by 2084

Abstract

Overexpression of the neurotensin receptor type 1 (NTS₁R), a peptide receptor located at the plasma membrane, has been reported for a variety of malignant tumors. Thus, targeting the NTS₁R with ¹⁸F- or ⁶⁸Ga-labeled ligands is considered a straightforward approach towards in vivo imaging of NTS₁R-expressing tumors via positron emission tomography (PET). The development of suitable peptidic NTS₁R PET ligands derived from neurotensin is challenging due to proteolytic degradation. In this study, we prepared a series of NTS₁R PET ligands based on the C-terminal fragment of neurotensin (NT(8–13), Arg⁸-Arg⁹-Pro¹⁰-Tyr¹¹-Ile¹²-Leu¹³) by attachment of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) via an N^ω-carbamoylated arginine side chain. Insertion of Ga³⁺ in the DOTA chelator gave potential PET ligands that were evaluated concerning NTS₁R affinity (range of K_i values: 1.2–21 nM) and plasma stability. Four candidates were labeled with ⁶⁸Ga³⁺ and used for biodistribution studies in HT-29 tumor-bearing mice. [⁶⁸Ga]UR-LS130 ([⁶⁸Ga]56), containing an N-terminal methyl group and a β,β-dimethylated tyrosine instead of Tyr¹¹, showed the highest in vivo stability and afforded a tumor-to-muscle ratio of 16 at 45 min p.i. Likewise, dynamic PET scans enabled a clear tumor visualization. The accumulation of [⁶⁸Ga]56 in the tumor was NTS₁R-mediated, as proven by blocking studies. Full article

(This article belongs to the Special Issue Recent Trends in PET/CT Tracer Development and Multimodal Imaging)

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15 pages, 3549 KiB

Open AccessArticle

Non-Invasive Characterization of Experimental Bone Metastasis in Obesity Using Multiparametric MRI and PET/CT

by Gasper Gregoric, Anastasia Gaculenko, Lisa Nagel, Vanessa Popp, Simone Maschauer, Olaf Prante, Marc Saake, Georg Schett, Michael Uder, Stephan Ellmann, Aline Bozec and Tobias Bäuerle

Cancers 2022, 14(10), 2482; https://doi.org/10.3390/cancers14102482 - 18 May 2022

Cited by 1 | Viewed by 1998

Abstract

The growth of primary tumors and metastases is associated with excess body fat. In bone metastasis formation, the bone marrow microenvironment, and particularly adipocytes, play a pivotal role as growth mediators of disseminated tumor cells in the bone marrow. The aim of the present study is to non-invasively characterize the pathophysiologic processes in experimental bone metastasis resulting from accelerated tumor progression within adipocyte-rich bone marrow using multimodal imaging from magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT). To achieve this, we have employed small animal models after the administration of MDA-MB 231 breast cancer and B16F10 melanoma cells into the bone of nude rats or C57BL/6 mice, respectively. After tumor cell inoculation, ultra-high field MRI and µPET/CT were used to assess functional and metabolic parameters in the bone marrow of control animals (normal diet, ND), following a high-fat diet (HFD), and/or treated with the peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist bisphenol-A-diglycidylether (BADGE), respectively. In the bone marrow of nude rats, dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI), as well as [¹⁸F]fluorodeoxyglucose-PET/CT([¹⁸F]FDG-PET/CT), was performed 10, 20, and 30 days after tumor cell inoculation, followed by immunohistochemistry. DCE-MRI parameters associated with blood volume, such as area under the curve (AUC), were significantly increased in bone metastases in the HFD group 30 days after tumor cell inoculation as compared to controls (p < 0.05), while the DWI parameter apparent diffusion coefficient (ADC) was not significantly different between the groups. [¹⁸F]FDG-PET/CT showed an enhanced glucose metabolism due to increased standardized uptake value (SUV) at day 30 after tumor cell inoculation in animals that received HFD (p < 0.05). BADGE treatment resulted in the inversion of quantitative DCE-MRI and [¹⁸F]FDG-PET/CT data, namely a significant decrease in AUC and SUV in HFD-fed animals as compared to ND-fed controls (p < 0.05). Finally, immunohistochemistry and qPCR confirmed the HFD-induced stimulation in vascularization and glucose activity in murine bone metastases. In conclusion, multimodal and multiparametric MRI and [¹⁸F]FDG-PET/CT were able to derive quantitative parameters in bone metastases, revealing an increase in vascularization and glucose metabolism following HFD. Thus, non-invasive imaging may serve as a biomarker for assessing the pathophysiology of bone metastasis in obesity, opening novel options for therapy and treatment monitoring by MRI and [¹⁸F]FDG-PET/CT. Full article

(This article belongs to the Special Issue Recent Trends in PET/CT Tracer Development and Multimodal Imaging)

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28 pages, 5851 KiB

Open AccessArticle

Side-by-Side Comparison of Five Chelators for ⁸⁹Zr-Labeling of Biomolecules: Investigation of Chemical/Radiochemical Properties and Complex Stability

by Helen Damerow, Ralph Hübner, Benedikt Judmann, Ralf Schirrmacher, Björn Wängler, Gert Fricker and Carmen Wängler

Cancers 2021, 13(24), 6349; https://doi.org/10.3390/cancers13246349 - 17 Dec 2021

Cited by 13 | Viewed by 3333

Abstract

In this work, five different chelating agents, namely DFO, CTH-36, DFO*, 3,4,3-(LI-1,2-HOPO) and DOTA-GA, were compared with regard to the relative kinetic inertness of their corresponding ⁸⁹Zr complexes to evaluate their potential for in vivo application and stable ⁸⁹Zr complexation. The chelators were identically functionalized with tetrazines, enabling a fully comparable, efficient, chemoselective and biorthogonal conjugation chemistry for the modification of any complementarily derivatized biomolecules of interest. A small model peptide of clinical relevance (TCO-c(RGDfK)) was derivatized via iEDDA click reaction with the developed chelating agents (TCO = trans-cyclooctene and iEDDA = inverse electron demand Diels-Alder). The bioconjugates were labeled with ⁸⁹Zr⁴⁺, and their radiochemical properties (labeling conditions and efficiency), logD_(7.4), as well as the relative kinetic inertness of the formed complexes, were compared. Furthermore, density functional theory (DFT) calculations were conducted to identify potential influences of chelator modification on complex formation and geometry. The results of the DFT studies showed—apart from the DOTA-GA derivative—no significant influence of chelator backbone functionalization or the conjugation of the chelator tetrazines by iEDDA. All tetrazines could be efficiently introduced into c(RGDfK), demonstrating the high suitability of the agents for efficient and chemoselective bioconjugation. The DFO-, CTH-36- and DFO*-modified c(RGDfK) peptides showed a high radiolabeling efficiency under mild reaction conditions and complete ⁸⁹Zr incorporation within 1 h, yielding the ⁸⁹Zr-labeled analogs as homogenous products. In contrast, 3,4,3-(LI-1,2-HOPO)-c(RGDfK) required considerably prolonged reaction times of 5 h for complete radiometal incorporation and yielded several different ⁸⁹Zr-labeled species. The labeling of the DOTA-GA-modified peptide was not successful at all. Compared to [⁸⁹Zr]Zr-DFO-, [⁸⁹Zr]Zr-CTH-36- and [⁸⁹Zr]Zr-DFO*-c(RGDfK), the corresponding [⁸⁹Zr]Zr-3,4,3-(LI-1,2-HOPO) peptide showed a strongly increased lipophilicity. Finally, the relative stability of the ⁸⁹Zr complexes against the EDTA challenge was investigated. The [⁸⁹Zr]Zr-DFO complex showed—as expected—a low kinetic inertness. Unexpectedly, also, the [⁸⁹Zr]Zr-CTH-36 complex demonstrated a high susceptibility against the challenge, limiting the usefulness of CTH-36 for stable ⁸⁹Zr complexation. Only the [⁸⁹Zr]Zr-DFO* and the [⁸⁹Zr]Zr-3,4,3-(LI-1,2-HOPO) complexes demonstrated a high inertness, qualifying them for further comparative in vivo investigation to determine the most appropriate alternative to DFO for clinical application. Full article

(This article belongs to the Special Issue Recent Trends in PET/CT Tracer Development and Multimodal Imaging)

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18 pages, 4369 KiB

Open AccessArticle

Evaluation of 3-l- and 3-d-[¹⁸F]Fluorophenylalanines as PET Tracers for Tumor Imaging

by Felicia Krämer, Benedikt Gröner, Chris Hoffmann, Austin Craig, Melanie Brugger, Alexander Drzezga, Marco Timmer, Felix Neumaier, Boris D. Zlatopolskiy, Heike Endepols and Bernd Neumaier

Cancers 2021, 13(23), 6030; https://doi.org/10.3390/cancers13236030 - 30 Nov 2021

Cited by 4 | Viewed by 1826

Abstract

Purpose: The preclinical evaluation of 3-l- and 3-d-[¹⁸F]FPhe in comparison to [¹⁸F]FET, an established tracer for tumor imaging. Methods: In vitro studies were conducted with MCF-7, PC-3, and U87 MG human tumor cell lines. In vivo µPET studies were conducted in healthy rats with/without the inhibition of peripheral aromatic l-amino acid decarboxylase by benserazide pretreatment (n = 3 each), in mice bearing subcutaneous MCF-7 or PC-3 tumor xenografts (n = 10), and in rats bearing orthotopic U87 MG tumor xenografts (n = 14). Tracer accumulation was quantified by SUV_max, SUV_mean and tumor-to-brain ratios (TBrR). Results: The uptake of 3-l-[¹⁸F]FPhe in MCF-7 and PC-3 cells was significantly higher relative to [¹⁸F]FET. The uptake of all three tracers was significantly reduced by the suppression of amino acid transport systems L or ASC. 3-l-[¹⁸F]FPhe but not 3-d-[¹⁸F]FPhe exhibited protein incorporation. In benserazide-treated healthy rats, brain uptake after 42–120 min was significantly higher for 3-d-[¹⁸F]FPhe vs. 3-l-[¹⁸F]FPhe. [¹⁸F]FET showed significantly higher uptake into subcutaneous MCF-7 tumors (52–60 min p.i.), while early uptake into orthotopic U87 MG tumors was significantly higher for 3-l-[¹⁸F]FPhe (SUV_max: 3-l-[¹⁸F]FPhe, 107.6 ± 11.3; 3-d-[¹⁸F]FPhe, 86.0 ± 4.3; [¹⁸F]FET, 90.2 ± 7.7). Increased tumoral expression of LAT1 and ASCT2 was confirmed immunohistologically. Conclusion: Both novel tracers enable accurate tumor delineation with an imaging quality comparable to [¹⁸F]FET. Full article

(This article belongs to the Special Issue Recent Trends in PET/CT Tracer Development and Multimodal Imaging)

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Review

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29 pages, 17797 KiB

Open AccessReview

Application of PET/MRI in Gynecologic Malignancies

by Sheida Ebrahimi, Elin Lundström, Summer J. Batasin, Elisabeth Hedlund, Karin Stålberg, Eric C. Ehman, Vipul R. Sheth, Negaur Iranpour, Stephane Loubrie, Alexandra Schlein and Rebecca Rakow-Penner

Cancers 2024, 16(8), 1478; https://doi.org/10.3390/cancers16081478 - 12 Apr 2024

Viewed by 597

Abstract

The diagnosis, treatment, and management of gynecologic malignancies benefit from both positron emission tomography/computed tomography (PET/CT) and MRI. PET/CT provides important information on the local extent of disease as well as diffuse metastatic involvement. MRI offers soft tissue delineation and loco-regional disease involvement. The combination of these two technologies is key in diagnosis, treatment planning, and evaluating treatment response in gynecological malignancies. This review aims to assess the performance of PET/MRI in gynecologic cancer patients and outlines the technical challenges and clinical advantages of PET/MR systems when specifically applied to gynecologic malignancies. Full article

(This article belongs to the Special Issue Recent Trends in PET/CT Tracer Development and Multimodal Imaging)

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18 pages, 5211 KiB

Open AccessReview

Diagnostic Value of Radiolabelled Somatostatin Analogues for Neuroendocrine Tumour Diagnosis: The Benefits and Drawbacks of [⁶⁴Cu]Cu-DOTA-TOC

by Nasim Vahidfar, Saeed Farzanehfar, Mehrshad Abbasi, Siroos Mirzaei, Ebrahim S. Delpassand, Farzad Abbaspour, Yalda Salehi, Hans Jürgen Biersack and Hojjat Ahmadzadehfar

Cancers 2022, 14(8), 1914; https://doi.org/10.3390/cancers14081914 - 10 Apr 2022

Cited by 4 | Viewed by 2391

Abstract

Neuroendocrine tumours (NETs) arise from secondary epithelial cell lines in the gastrointestinal or respiratory system organs. The rate of development of these tumours varies from an indolent to an aggressive course, typically being initially asymptomatic. The identification of these tumours is difficult, particularly because the primary tumour is often small and undetectable by conventional anatomical imaging. Consequently, diagnosis of NETs is complicated and has been a significant challenge until recently. In the last 30 years, the advent of novel nuclear medicine diagnostic procedures has led to a substantial increase in NET detection. Great varieties of exclusive single photon emission computed tomography (SPECT) and positron emission tomography (PET) radiopharmaceuticals for detecting NETs are being applied successfully in clinical settings, including [¹¹¹In]In-pentetreotide, [^99mTc]Tc-HYNIC-TOC/TATE, [⁶⁸Ga]Ga-DOTA-TATE, and [⁶⁴Cu]Cu-DOTA-TOC/TATE. Among these tracers for functional imaging, PET radiopharmaceuticals are clearly and substantially superior to planar or SPECT imaging radiopharmaceuticals. The main advantages include higher resolution, better sensitivity and increased lesion-to-background uptake. An advantage of diagnosis with a radiopharmaceutical is the capacity of theranostics to provide concomitant diagnosis and treatment with particulate radionuclides, such as beta and alpha emitters including Lutetium-177 (¹⁷⁷Lu) and Actinium-225 (²²⁵Ac). Due to these unique challenges involved with diagnosing NETs, various PET tracers have been developed. This review compares the clinical characteristics of radiolabelled somatostatin analogues for NET diagnosis, focusing on the most recently FDA-approved [⁶⁴Cu]Cu-DOTA-TATE as a state-of-the art NET-PET/CT radiopharmaceutical. Full article

(This article belongs to the Special Issue Recent Trends in PET/CT Tracer Development and Multimodal Imaging)

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