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Design, Synthesis and Evaluation of Theranostic Radiopharmaceuticals

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 9835

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Special Issue Editor

Dr. Zhengxing Zhang

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Guest Editor

Yale School of Medicine, Yale University, New Haven, CT, USA
Interests: molecular imaging; radiopharmaceutical; PET/CT; SPECT/CT; oncology

Special Issue Information

Dear Colleagues,

Theanostics bridging diagnosis and therapy enables prompt therapy planning, post therapy assessment and personalized treatment, therefore, becomes increasingly attractive especially in cancer therapy with nuclear medicine. Theranostic radiopharmaceuticals consist of a pair of specific tumor receptor targeting pharmacophore labeled with either diagnostic radio isotopes (¹⁸F, ⁶⁸Ga, etc.) or theranostic radio isotopes (¹⁷⁷Lu, ⁹⁹Y, ²²⁵Ac, etc.). The history of theranostic radiopharmaceuticals can be dated back to ¹²³I /¹³¹I-iodide for the treatment of thyroid disease and ¹²³I /¹³¹I-IMBG for the treatment of adrenergic tumors. Recent development milestones include ⁶⁸Ga/¹⁷⁷Lu-DOTATATE for the treatment of neuroendocrine tumors and ⁶⁸Ga/¹⁷⁷Lu-PSMA617 for the treatment of prostate cancer. The design, synthesis and evaluation of theranostic radiopharmaceuticals are of great and continuous interest of nuclear medicine physicians and radiochemists.

Herein, the editorial team of this special issue cordially call for high quality research, review and outlook papers in the field of theranostic radiopharmaceuticals. Your kind supports are highly appreciated

Dr. Zhengxing Zhang
Guest Editor

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Keywords

theranostic
radiopharmaceutical
PET imaging
SPECT imaging
therapy
diagnosis

Published Papers (4 papers)

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Research

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16 pages, 2716 KiB

Open AccessArticle

Preclinical Evaluation of [^155/161Tb]Tb-Crown-TATE—A Novel SPECT Imaging Theranostic Agent Targeting Neuroendocrine Tumours

by Luke Wharton, Scott W. McNeil, Helen Merkens, Zheliang Yuan, Michiel Van de Voorde, Gokce Engudar, Aidan Ingham, Helena Koniar, Cristina Rodríguez-Rodríguez, Valery Radchenko, Maarten Ooms, Peter Kunz, François Bénard, Paul Schaffer and Hua Yang

Molecules 2023, 28(7), 3155; https://doi.org/10.3390/molecules28073155 - 01 Apr 2023

Cited by 4 | Viewed by 2645

Abstract

Terbium radioisotopes (¹⁴⁹Tb, ¹⁵²Tb, ¹⁵⁵Tb, ¹⁶¹Tb) offer a unique class of radionuclides which encompass all four medicinally relevant nuclear decay modalities (α, β⁺, γ, β⁻/e⁻), and show high potential for the development of element-matched theranostic radiopharmaceuticals. The goal of this study was to design, synthesise, and evaluate the suitability of crown-TATE as a new peptide-conjugate for radiolabelling of [¹⁵⁵Tb]Tb³⁺ and [¹⁶¹Tb]Tb³⁺, and to assess the imaging and pharmacokinetic properties of each radiotracer in tumour-bearing mice. [¹⁵⁵Tb]Tb-crown-TATE and [¹⁶¹Tb]Tb-crown-TATE were prepared efficiently under mild conditions, and exhibited excellent stability in human serum (>99.5% RCP over 7 days). Longitudinal SPECT/CT images were acquired for ¹⁵⁵Tb- and ¹⁶¹Tb- labelled crown-TATE in male NRG mice bearing AR42J tumours. The radiotracers, [¹⁵⁵Tb]Tb-crown-TATE and [¹⁶¹Tb]Tb-crown-TATE, showed high tumour targeting (32.6 and 30.0 %ID/g, respectively) and minimal retention in non-target organs at 2.5 h post-administration. Biodistribution studies confirmed the SPECT/CT results, showing high tumour uptake (38.7 ± 8.0 %ID/g and 38.5 ± 3.5 %ID/g, respectively) and favourable tumour-to-background ratios. Blocking studies further confirmed SSTR2-specific tumour accumulation. Overall, these findings suggest that crown-TATE has great potential for element-matched molecular imaging and radionuclide therapy using ¹⁵⁵Tb and ¹⁶¹Tb. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Theranostic Radiopharmaceuticals)

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15 pages, 2690 KiB

Open AccessArticle

⁶⁸Ga-Labeled [Thz¹⁴]Bombesin(7–14) Analogs: Promising GRPR-Targeting Agonist PET Tracers with Low Pancreas Uptake

by Lei Wang, Ivica Jerolim Bratanovic, Zhengxing Zhang, Hsiou-Ting Kuo, Helen Merkens, Jutta Zeisler, Chengcheng Zhang, Ruiyan Tan, François Bénard and Kuo-Shyan Lin

Molecules 2023, 28(4), 1977; https://doi.org/10.3390/molecules28041977 - 20 Feb 2023

Cited by 1 | Viewed by 1691

Abstract

With overexpression in various cancers, the gastrin-releasing peptide receptor (GRPR) is a promising target for cancer imaging and therapy. However, the high pancreas uptake of reported GRPR-targeting radioligands limits their clinical application. Our goal was to develop ⁶⁸Ga-labeled agonist tracers for detecting GRPR-expressing tumors with positron emission tomography (PET), and compare them with the clinically validated agonist PET tracer, [⁶⁸Ga]Ga-AMBA. Ga-TacBOMB2, TacBOMB3, and TacBOMB4, derived from [Thz¹⁴]Bombesin(7–14), were confirmed to be GRPR agonists by a calcium mobilization study, and their binding affinities (K_i(GRPR)) were determined to be 7.62 ± 0.19, 6.02 ± 0.59, and 590 ± 36.5 nM, respectively, via in vitro competition binding assays. [⁶⁸Ga]Ga-TacBOMB2, [⁶⁸Ga]Ga-TacBOMB3, and [⁶⁸Ga]Ga-AMBA clearly visualized PC-3 tumor xenografts in a PET imaging study. [⁶⁸Ga]Ga-TacBOMB2 showed comparable tumor uptake but superior tumor-to-background contrast ratios when compared to [⁶⁸Ga]Ga-AMBA. Moreover, [⁶⁸Ga]Ga-TacBOMB2 and [⁶⁸Ga]Ga-TacBOMB3 showed a much lower rate of uptake in the pancreas (1.30 ± 0.14 and 2.41 ± 0.72%ID/g, respectively) than [⁶⁸Ga]Ga-AMBA (62.4 ± 4.26%ID/g). In conclusion, replacing Met¹⁴ in the GRPR-targeting sequence with Thz¹⁴ retains high GRPR-binding affinity and agonist properties. With good tumor uptake and tumor-to-background uptake ratios, [⁶⁸Ga]Ga-TacBOMB2 is promising for detecting GRPR-expressing tumors. The much lower pancreas uptake of [⁶⁸Ga]Ga-TacBOMB2 and [⁶⁸Ga]Ga-TacBOMB3 suggests that [Thz¹⁴]Bombesin(7–14) is a promising targeting vector for the design of GRPR-targeting radiopharmaceuticals, especially for radioligand therapy application. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Theranostic Radiopharmaceuticals)

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17 pages, 3464 KiB

Open AccessArticle

Synthesis and Preclinical Evaluation of Three Novel ⁶⁸Ga-Labeled Bispecific PSMA/FAP-Targeting Tracers for Prostate Cancer Imaging

by Arsyangela Verena, Zhengxing Zhang, Hsiou-Ting Kuo, Helen Merkens, Jutta Zeisler, Ryan Wilson, Shreya Bendre, Antonio A. W. L. Wong, François Bénard and Kuo-Shyan Lin

Molecules 2023, 28(3), 1088; https://doi.org/10.3390/molecules28031088 - 21 Jan 2023

Cited by 10 | Viewed by 2620

Abstract

Tumor heterogeneity limits the efficacy and reliability of monospecific radiopharmaceuticals in prostate cancer diagnosis and therapy. To overcome this limitation and improve lesion detection sensitivity, we developed and evaluated three bispecific radiotracers that can target both prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), which are the two key proteins overexpressed in prostate cancer. Three FAP-targeting ligands with various linker lengths were synthesized through multistep organic synthesis, and then connected to the PSMA-targeting motif. IC₅₀(PSMA) and IC₅₀(FAP) values of Ga-complexed bispecific ligands, Ga-AV01017, Ga-AV01030, and Ga-AV01038 were 25.2–71.6 and 1.25–2.74 nM, respectively. The uptake values in PSMA-expressing LNCaP tumor xenografts were 4.38 ± 0.55, 5.17 ± 0.51, and 4.25 ± 0.86 %ID/g for [⁶⁸Ga]Ga-AV01017, [⁶⁸Ga]Ga-AV01030, and [⁶⁸Ga]Ga-AV01038, respectively, which were lower than the monospecific PSMA-targeting tracer [⁶⁸Ga]Ga-HTK03041 (23.1 ± 6.11 %ID/g). The uptake values in FAP-expressing HEK293T:hFAP tumor xenografts were 2.99 ± 0.37, 3.69 ± 0.81, 3.64 ± 0.83 %ID/g for [⁶⁸Ga]Ga-AV01017, [⁶⁸Ga]Ga-AV01030, and [⁶⁸Ga]Ga-AV01038, respectively, which were also lower than the monospecific FAP-targeting tracer, [⁶⁸Ga]Ga-FAPI-04 (12.5 ± 2.00 %ID/g). We observed that the bispecific tracers had prolonged blood retention, in which tracers with a longer linker tend to have a higher blood uptake and lower tumor uptake. Further investigations are needed to optimize the linker selection to generate promising bispecific PSMA/FAP-targeting tracers for prostate cancer imaging. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Theranostic Radiopharmaceuticals)

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Review

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21 pages, 2583 KiB

Open AccessReview

CXCR4-Targeted Radiopharmaceuticals for the Imaging and Therapy of Malignant Tumors

by Jingjing Yu, Xu Zhou and Langtao Shen

Molecules 2023, 28(12), 4707; https://doi.org/10.3390/molecules28124707 - 12 Jun 2023

Viewed by 2048

Abstract

C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or CD184, is a 7-transmembrane helix G-protein-coupled receptor that is encoded by the CXCR4 gene. Involved in various physiological processes, CXCR4 could form an interaction with its endogenous partner, chemokine ligand 12 (CXCL12), which is also named SDF-1. In the past several decades, the CXCR4/CXCL12 couple has attracted a large amount of research interest due to its critical functions in the occurrence and development of refractory diseases, such as HIV infection, inflammatory diseases, and metastatic cancer, including breast cancer, gastric cancer, and non-small cell lung cancer. Furthermore, overexpression of CXCR4 in tumor tissues was shown to have a high correlation with tumor aggressiveness and elevated risks of metastasis and recurrence. The pivotal roles of CXCR4 have encouraged an effort around the world to investigate CXCR4-targeted imaging and therapeutics. In this review, we would like to summarize the implementation of CXCR4-targeted radiopharmaceuticals in the field of various kinds of carcinomas. The nomenclature, structure, properties, and functions of chemokines and chemokine receptors are briefly introduced. Radiopharmaceuticals that could target CXCR4 will be described in detail according to their structure, such as pentapeptide-based structures, heptapeptide-based structures, nonapeptide-based structures, etc. To make this review a comprehensive and informative article, we would also like to provide the predictive prospects for the CXCR4-targeted species in future clinical development. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Theranostic Radiopharmaceuticals)

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