Inverse electron demand Diels–Alder reactions in chemical biology

B. L. Oliveira, Z. Guo and G. J. L. Bernardes

Chem. Soc. Rev., 2017, 46, 4895
DOI: 10.1039/C7CS00184C

Harnessing nanoparticles and bioorthogonal chemistries for improving precision of nuclear medicine

Gayathri R. Ediriweera, Mengdie Li, Nicholas L. Fletcher, Zachary H. Houston, Muneer Ahamed, Idriss Blakey and Kristofer J. Thurecht

Biomater. Sci., 2025, 13, 2297
DOI: 10.1039/D4BM01387E

Detecting hypoxia in vitro using 18F-pretargeted IEDDA “click” chemistry in live cells

Louis Allott, Cen Chen, Marta Braga, Sau Fung Jacob Leung, Ning Wang, Chris Barnes, Diana Brickute, Laurence Carroll and Eric O. Aboagye

RSC Adv., 2021, 11, 20335
DOI: 10.1039/D1RA02482E

Enabling the formation of native mAb, Fab′ and Fc-conjugates using a bis-disulfide bridging reagent to achieve tunable payload-to-antibody ratios (PARs)

Fabien Thoreau, Léa N. C. Rochet, James R. Baker and Vijay Chudasama

Chem. Sci., 2023, 14, 3752
DOI: 10.1039/D2SC06318B

Micro-flow photosynthesis of new dienophiles for inverse-electron-demand Diels–Alder reactions. Potential applications for pretargeted in vivo PET imaging

Emilie M. F. Billaud, Elnaz Shahbazali, Muneer Ahamed, Frederik Cleeren, Timothy Noël, Michel Koole, Alfons Verbruggen, Volker Hessel and Guy Bormans

Chem. Sci., 2017, 8, 1251
DOI: 10.1039/C6SC02933G

Development of68Ga-labelled ultrasound microbubbles for whole-body PET imaging

Javier Hernández-Gil, Marta Braga, Bethany I. Harriss, Laurence S. Carroll, Chee Hau Leow, Meng-Xing Tang, Eric O. Aboagye and Nicholas J. Long

Chem. Sci., 2019, 10, 5603
DOI: 10.1039/C9SC00684B

Current advances in ligand design for inorganic positron emission tomography tracers 68Ga, 64Cu, 89Zr and 44Sc

Thomas W. Price, John Greenman and Graeme J. Stasiuk

Dalton Trans., 2016, 45, 15702
DOI: 10.1039/C5DT04706D

Lanthanide–tetrazine probes for bio-imaging and click chemistry

Benjamin Woolley, Yue Wu, Li Xiong, Ho-Fai Chau, Junhui Zhang, Ga-Lai Law, Ka-Leung Wong and Nicholas J. Long

Chem. Sci., 2025, 16, 3588
DOI: 10.1039/D4SC02335H

Targeted and modular architectural polymers employing bioorthogonal chemistry for quantitative therapeutic delivery

Gayathri R. Ediriweera, Joshua D. Simpson, Adrian V. Fuchs, Taracad K. Venkatachalam, Matthias Van De Walle, Christopher B. Howard, Stephen M. Mahler, James P. Blinco, Nicholas L. Fletcher, Zachary H. Houston, Craig A. Bell and Kristofer J. Thurecht

Chem. Sci., 2020, 11, 3268
DOI: 10.1039/D0SC00078G

[68Ga]Ga-THP-tetrazine for bioorthogonal click radiolabelling: pretargeted PET imaging of liposomal nanomedicines

Aishwarya Mishra, Amaia Carrascal-Miniño, Jana Kim and Rafael T. M. de Rosales

RSC Chem. Biol., 2024, 5, 622
DOI: 10.1039/D4CB00039K

Pretargeted Nuclear Imaging and Radioimmunotherapy Based on the Inverse Electron-Demand Diels–Alder Reaction and Key Factors in the Pretargeted Synthetic Design

Lin Qiu, Wujian Mao, Hongyan Yin, Hui Tan, Dengfeng Cheng and Hongcheng Shi

Contrast Media & Molecular Imaging, 2019, 2019, 1
DOI: 10.1155/2019/9182476

Development of radioimmunoconjugate for diagnosis and management of head-and-neck subclinical cancer and colorectal carcinoma

Raquel Benedetto, Adriana Vidal Fernandes Massicano, Jefferson Jesus Silva, Cristian Antonio Wieczorek Villas Boas, Jair Mengatti and Elaine Bortoleti de Araújo

Braz. J. Pharm. Sci., 2018, 53
DOI: 10.1590/s2175-97902017000417039

Diagnosis of Glioblastoma by Immuno-Positron Emission Tomography

Eduardo Ruiz-López, Juan Calatayud-Pérez, Irene Castells-Yus, María José Gimeno-Peribáñez, Noelia Mendoza-Calvo, Miguel Ángel Morcillo and Alberto J. Schuhmacher

Cancers, 2021, 14, 74
DOI: 10.3390/cancers14010074

Design, Synthesis, Conjugation, and Reactivity of Novel trans,trans-1,5-Cyclooctadiene-Derived Bioorthogonal Linkers

Beatrice Longo, Chiara Zanato, Monica Piras, Sergio Dall’Angelo, Albert D. Windhorst, Danielle J. Vugts, Massimiliano Baldassarre and Matteo Zanda

Bioconjugate Chem., 2020, 31, 2201
DOI: 10.1021/acs.bioconjchem.0c00375

Radiochemistry for positron emission tomography

Jian Rong, Achi Haider, Troels E. Jeppesen, Lee Josephson and Steven H. Liang

Nat Commun, 2023, 14
DOI: 10.1038/s41467-023-36377-4

The Inverse Electron Demand Diels‐Alder Reaction Between Tetrazine and Trans‐Cyclooctene for Pretargeted Bioimaging Applications

Aihua Liao, Wei Du and Huanghao Yang

Analysis & Sensing, 2024, 4
DOI: 10.1002/anse.202300053

Recent Advances in Targeting Nuclear Molecular Imaging Driven by Tetrazine Bioorthogonal Chemistry

Ping Dong, Xueyi Wang, Junwei Zheng, Xiaoyang Zhang, Yiwen Li, Haoxing Wu and Lin Li

CMC, 2020, 27, 3924
DOI: 10.2174/1386207322666190702105829

Pretargeting in nuclear imaging and radionuclide therapy: Improving efficacy of theranostics and nanomedicines

E. Johanna L. Stéen, Patricia E. Edem, Kamilla Nørregaard, Jesper T. Jørgensen, Vladimir Shalgunov, Andreas Kjaer and Matthias M. Herth

Biomaterials, 2018, 179, 209
DOI: 10.1016/j.biomaterials.2018.06.021

Development and Evaluation of an 18F-Radiolabeled Monocyclam Derivative for Imaging CXCR4 Expression

Diana Brickute, Marta Braga, Maciej A. Kaliszczak, Chris Barnes, Doreen Lau, Laurence Carroll, Elizabeth Stevens, Sebastian Trousil, Israt S. Alam, Quang-Dé Nguyen and Eric O. Aboagye

Mol. Pharmaceutics, 2019, 16, 2106
DOI: 10.1021/acs.molpharmaceut.9b00069

Exploring Structural Parameters for Pretargeting Radioligand Optimization

Jan-Philip Meyer, Paul Kozlowski, James Jackson, Kristen M. Cunanan, Pierre Adumeau, Thomas R. Dilling, Brian M. Zeglis and Jason S. Lewis

J. Med. Chem., 2017, 60, 8201
DOI: 10.1021/acs.jmedchem.7b01108

Clickable Radiocomplexes With Trivalent Radiometals for Cancer Theranostics: In vitro and in vivo Studies

Alice D'Onofrio, Francisco Silva, Lurdes Gano, Urszula Karczmarczyk, Renata Mikołajczak, Piotr Garnuszek and António Paulo

Front. Med., 2021, 8
DOI: 10.3389/fmed.2021.647379

Chemical tags for site-specific fluorescent labeling of biomolecules

Christoph Freidel, Stefka Kaloyanova and Kalina Peneva

Amino Acids, 2016, 48, 1357
DOI: 10.1007/s00726-016-2204-5

Emerging formats for next-generation antibody drug conjugates

Mahendra P Deonarain, Gokhan Yahioglu, Ioanna Stamati and Jared Marklew

Expert Opinion on Drug Discovery, 2015, 10, 463
DOI: 10.1517/17460441.2015.1025049

In Vivo Pretargeting Based on Cysteine-Selective Antibody Modification with IEDDA Bioorthogonal Handles for Click Chemistry

Vera F. C. Ferreira, Bruno L. Oliveira, Alice D’Onofrio, Carlos M. Farinha, Lurdes Gano, António Paulo, Gonçalo J. L. Bernardes and Filipa Mendes

Bioconjugate Chem., 2021, 32, 121
DOI: 10.1021/acs.bioconjchem.0c00551

Rapid Access to Potent Bispecific T Cell Engagers Using Biogenic Tyrosine Click Chemistry

Irene Shajan, Léa N. C. Rochet, Shannon R. Tracey, Bianka Jackowska, Rania Benazza, Oscar Hernandez-Alba, Sarah Cianférani, Christopher J. Scott, Floris L. van Delft, Vijay Chudasama and Bauke Albada

Bioconjugate Chem., 2023, 34, 2215
DOI: 10.1021/acs.bioconjchem.3c00357

Inverse‐Electron‐Demand Diels–Alder Reactions: Principles and Applications

Zhuang Mao Png, Huining Zeng, Qun Ye and Jianwei Xu

Chemistry An Asian Journal, 2017, 12, 2142
DOI: 10.1002/asia.201700442

Pretargeted nuclear imaging and radioimmunotherapy based on the inverse electron-demand Diels-Alder reaction

Yirong Zhu, Jiang Jiang, Kairu Ni, Jiaxi You, Zengli Liu and Zhihui Hong

Nuclear Medicine Communications, 2025
DOI: 10.1097/MNM.0000000000002040

Expanding the Applicability of the Metal Labeling of Biomolecules by the RIKEN Click Reaction: A Case Study with Gallium‐68 Positron Emission Tomography

Yuka Nakamoto, Ambara R. Pradipta, Hidefumi Mukai, Maki Zouda, Yasuyoshi Watanabe, Almira Kurbangalieva, Peni Ahmadi, Yoshiyuki Manabe, Koichi Fukase and Katsunori Tanaka

ChemBioChem, 2018, 19, 2055
DOI: 10.1002/cbic.201800335

Trans-cyclooctene—a Swiss army knife for bioorthogonal chemistry: exploring the synthesis, reactivity, and applications in biomedical breakthroughs

Karuna Adhikari, Maarten Vanermen, Gustavo Da Silva, Tim Van den Wyngaert, Koen Augustyns and Filipe Elvas

EJNMMI radiopharm. chem., 2024, 9
DOI: 10.1186/s41181-024-00275-x

Pretargeted PET Imaging Using a Bioorthogonal 18F-Labeled trans-Cyclooctene in an Ovarian Carcinoma Model

Emilie M. F. Billaud, Sarah Belderbos, Frederik Cleeren, Wim Maes, Marlies Van de Wouwer, Michel Koole, Alfons Verbruggen, Uwe Himmelreich, Nick Geukens and Guy Bormans

Bioconjugate Chem., 2017, 28, 2915
DOI: 10.1021/acs.bioconjchem.7b00635

In Vivo Applications of Bioorthogonal Reactions: Chemistry and Targeting Mechanisms

Madonna M. A. Mitry, Francesca Greco and Helen M. I. Osborn

Chemistry A European J, 2023, 29
DOI: 10.1002/chem.202203942

Improved radiosynthesis and preliminary in vivo evaluation of the 11C-labeled tetrazine [11C]AE-1 for pretargeted PET imaging

E. Johanna L. Stéen, Jesper T. Jørgensen, Ida N. Petersen, Kamilla Nørregaard, Szabolcs Lehel, Vladimir Shalgunov, Alexander Birke, Patricia E. Edem, Elina T. L'Estrade, Hanne D. Hansen, Jonas Villadsen, Maria Erlandsson, Tomas Ohlsson, Abdolreza Yazdani, John F. Valliant, Jesper L. Kristensen, Matthias Barz, Gitte M. Knudsen, Andreas Kjær and Matthias M. Herth

Bioorganic & Medicinal Chemistry Letters, 2019, 29, 986
DOI: 10.1016/j.bmcl.2019.02.014

Synthesis and ex vivo biodistribution of two 68Ga-labeled tetrazine tracers: Comparison of pharmacokinetics

Elisavet Lambidis, Dave Lumén, Elina Koskipahta, Surachet Imlimthan, Brianda B. Lopez, Ana Isabel Fraguas Sánchez, Mirkka Sarparanta, R. Holland Cheng and Anu J. Airaksinen

Nuclear Medicine and Biology, 2022, 114-115, 151
DOI: 10.1016/j.nucmedbio.2022.05.004

Accessing Functionalized Tetrazines as Click Chemistry Tools: A Synthesis Guide for Chemists and Chemical Biologists

Lucas Moritz Bickem, Katerina Gavriel and Kevin Neumann

Eur J Org Chem, 2024, 27
DOI: 10.1002/ejoc.202301117

Modular Semisynthetic Approach to Generate T Cell-Dependent Bispecific Constructs from Recombinant IgG1 Antibodies

Irene Shajan, Léa N. C. Rochet, Shannon R. Tracey, Rania Benazza, Bianka Jackowska, Oscar Hernandez-Alba, Sarah Cianférani, Christopher J. Scott, Floris L. van Delft, Vijay Chudasama and Bauke Albada

Bioconjugate Chem., 2024
DOI: 10.1021/acs.bioconjchem.4c00309

In vivo imaging with antibodies and engineered fragments

Amanda C. Freise and Anna M. Wu

Molecular Immunology, 2015, 67, 142
DOI: 10.1016/j.molimm.2015.04.001

Facile, productive, and cost-effective synthesis of a novel tetrazine-based iron oxide nanoparticle for targeted image contrast agents and nanomedicines

Marco M. Meloni, Stephen Barton, Alexandru Chivu, Juan C. Kaski, Wenhui Song and Taigang He

J Nanopart Res, 2018, 20
DOI: 10.1007/s11051-018-4370-8

Pretargeting of internalizing trastuzumab and cetuximab with a 18F-tetrazine tracer in xenograft models

Outi Keinänen, Kimberly Fung, Jacob Pourat, Vilma Jallinoja, Delphine Vivier, NagaVara Kishore Pillarsetty, Anu J. Airaksinen, Jason S. Lewis, Brian M. Zeglis and Mirkka Sarparanta

EJNMMI Res, 2017, 7
DOI: 10.1186/s13550-017-0344-6

DOTA-tetrazine probes with modified linkers for tumor pretargeting

Tilman Läppchen, Raffaella Rossin, Tiemen R. van Mourik, Guillaume Gruntz, Freek J.M. Hoeben, Ron M. Versteegen, Henk M. Janssen, Johan Lub and Marc S. Robillard

Nuclear Medicine and Biology, 2017, 55, 19
DOI: 10.1016/j.nucmedbio.2017.09.001

Diagnosis of Pancreatic Ductal Adenocarcinoma by Immuno-Positron Emission Tomography

Ruth González-Gómez, Roberto A. Pazo-Cid, Luis Sarría, Miguel Ángel Morcillo and Alberto J. Schuhmacher

JCM, 2021, 10, 1151
DOI: 10.3390/jcm10061151

Site-Specific Covalent Conjugation of Modified mRNA by tRNA Guanine Transglycosylase

Fabian Ehret, Cun Yu Zhou, Seth C. Alexander, Dongyang Zhang and Neal K. Devaraj

Mol. Pharmaceutics, 2018, 15, 737
DOI: 10.1021/acs.molpharmaceut.7b00356

Recent Advances in the Development of Tetrazine Ligation Tools for Pretargeted Nuclear Imaging

Rocío García-Vázquez, Umberto Battisti and Matthias Herth

Pharmaceuticals, 2022, 15, 685
DOI: 10.3390/ph15060685

Targeting Infiltrating Myeloid Cells in Gastric Cancer Using a Pretargeted Imaging Strategy Based on Bio-Orthogonal Diels–Alder Click Chemistry and Comparison with 89Zr-Labeled Anti-CD11b Positron Emission Tomography Imaging

Yingying Zhang, Qingyu Lin, Tingting Wang, Dai Shi, Zhequan Fu, Zhan Si, Zhan Xu, Yuan Cheng, Hongcheng Shi and Dengfeng Cheng

Mol. Pharmaceutics, 2022, 19, 246
DOI: 10.1021/acs.molpharmaceut.1c00745

EGFR-targeted prodrug activation using bioorthogonal alkene-azide click-and-release chemistry

Jessica M. Fairhall, Júlia C. Camilli, Blake H. Gibson, Sarah Hook and Allan B. Gamble

Bioorganic & Medicinal Chemistry, 2021, 46, 116361
DOI: 10.1016/j.bmc.2021.116361

Evaluation of F-537-Tetrazine in a model for brain pretargeting imaging. Comparison to N-(3-[18F] fluoro-5-(1,2,4,5-tetrazin-3-yl)benzyl)propan-1-amine

Vladimir Shalgunov, Sara Lopes van den Broek, Ida Vang Andersen, Nakul R. Raval, Gabriela Schäfer, Matthias Barz, Matthias M. Herth and Umberto M. Battisti

Nuclear Medicine and Biology, 2024, 128-129, 108877
DOI: 10.1016/j.nucmedbio.2024.108877

Radiopharmaceuticals as probes to characterize tumour tissue

Israt S. Alam, Mubarik A. Arshad, Quang-Dé Nguyen and Eric O. Aboagye

Eur J Nucl Med Mol Imaging, 2015, 42, 537
DOI: 10.1007/s00259-014-2984-3

A covalent and cleavable antibody-DNA conjugation strategy for sensitive protein detection via immuno-PCR

Jessie A. G. L. van Buggenum, Jan P. Gerlach, Selma Eising, Lise Schoonen, Roderick A. P. M. van Eijl, Sabine E. J. Tanis, Mark Hogeweg, Nina C. Hubner, Jan C. van Hest, Kimberly M. Bonger and Klaas W. Mulder

Sci Rep, 2016, 6
DOI: 10.1038/srep22675

Inverse Electron-Demand Diels–Alder Bioorthogonal Reactions

Haoxing Wu and Neal K. Devaraj

Top Curr Chem (Z), 2016, 374
DOI: 10.1007/s41061-015-0005-z

Recent Advances in Bioorthogonal Click Chemistry for Efficient Synthesis of Radiotracers and Radiopharmaceuticals

Sajid Mushtaq, Seong-Jae Yun and Jongho Jeon

Molecules, 2019, 24, 3567
DOI: 10.3390/molecules24193567

Click Chemistry and Radiochemistry: The First 10 Years

Jan-Philip Meyer, Pierre Adumeau, Jason S. Lewis and Brian M. Zeglis

Bioconjugate Chem., 2016, 27, 2791
DOI: 10.1021/acs.bioconjchem.6b00561

A Plug-and-Play Approach for the De Novo Generation of Dually Functionalized Bispecifics

Antoine Maruani, Peter A. Szijj, Calise Bahou, João C. F. Nogueira, Stephen Caddick, James R. Baker and Vijay Chudasama

Bioconjugate Chem., 2020, 31, 520
DOI: 10.1021/acs.bioconjchem.0c00002

Optimization of Direct Aromatic 18F-Labeling of Tetrazines

Ida Vang Andersen, Rocío García-Vázquez, Umberto Maria Battisti and Matthias M. Herth

Molecules, 2022, 27, 4022
DOI: 10.3390/molecules27134022

Lipophilicity and Click Reactivity Determine the Performance of Bioorthogonal Tetrazine Tools in Pretargeted In Vivo Chemistry

E. Johanna L. Stéen, Jesper T. Jørgensen, Christoph Denk, Umberto M. Battisti, Kamilla Nørregaard, Patricia E. Edem, Klas Bratteby, Vladimir Shalgunov, Martin Wilkovitsch, Dennis Svatunek, Christian B. M. Poulie, Lars Hvass, Marina Simón, Thomas Wanek, Raffaella Rossin, Marc Robillard, Jesper L. Kristensen, Hannes Mikula, Andreas Kjaer and Matthias M. Herth

ACS Pharmacol. Transl. Sci., 2021, 4, 824
DOI: 10.1021/acsptsci.1c00007

The development of 177Lu-DOTA-CC-PSMA following a unified “Click Chemistry” protocol of synthesizing metal nuclide-conjugated radiopharmaceuticals

Xiaobei Zheng, Shuai Xue, Zhongqi Zhao, Shuxin Jin, Shuhua He, Lina Jia, Zheng Li, Christian Vanhove, Filip De Vos, Zijun Kuang, Tiantian Wang, Sara Neyt, Lan Zhang and Xiao Li

EJNMMI radiopharm. chem., 2024, 9
DOI: 10.1186/s41181-024-00287-7

A Pretargeted Imaging Strategy for EGFR-Positive Colorectal Carcinoma via Modulation of Tz-Radioligand Pharmacokinetics

Lin Qiu, Qingyu Lin, Zhan Si, Hui Tan, Guobing Liu, Jun Zhou, Tingting Wang, Yue Chen, Yingzhao Huang, Tao Yu, Mingzhi Jin, Dengfeng Cheng and Hongcheng Shi

Mol Imaging Biol, 2021, 23, 38
DOI: 10.1007/s11307-020-01539-z

Optimization of a Pretargeted Strategy for the PET Imaging of Colorectal Carcinoma via the Modulation of Radioligand Pharmacokinetics

Brian M. Zeglis, Christian Brand, Dalya Abdel-Atti, Kathryn E. Carnazza, Brendon E. Cook, Sean Carlin, Thomas Reiner and Jason S. Lewis

Mol. Pharmaceutics, 2015, 12, 3575
DOI: 10.1021/acs.molpharmaceut.5b00294

Click Reaction: An Applicable Radiolabeling Method for Molecular Imaging

Ji Young Choi and Byung Chul Lee

Nucl Med Mol Imaging, 2015, 49, 258
DOI: 10.1007/s13139-015-0377-6

Click‐Chemistry‐Mediated Rapid Microbubble Capture for Acute Thrombus Ultrasound Molecular Imaging

Tuantuan Wang, Chuxiao Yuan, Bingyang Dai, Yang Liu, Mingxi Li, Zhenqiang Feng, Qing Jiang, Zhihong Xu, Ningwei Zhao, Ning Gu and Fang Yang

ChemBioChem, 2017, 18, 1364
DOI: 10.1002/cbic.201700068

Reactivity of 7‐Azanorbornenes in Bioorthogonal Inverse Electron‐Demand Diels–Alder Reactions

Fumika Karaki, Kenji Ohgane, Hirotaka Imai, Kennosuke Itoh and Hideaki Fujii

Eur J Org Chem, 2017, 2017, 3815
DOI: 10.1002/ejoc.201700411

89Zr-DFO-Cetuximab as a Molecular Imaging Agent to Identify Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma

Raquel Benedetto, Adriana V.F. Massicano, Bryant K. Crenshaw, Renato Oliveira, Rui M. Reis, Elaine B. Araújo and Suzanne E. Lapi

Cancer Biotherapy and Radiopharmaceuticals, 2019, 34, 288
DOI: 10.1089/cbr.2018.2616

Development of Antibody Immuno-PET/SPECT Radiopharmaceuticals for Imaging of Oncological Disorders—An Update

Jonatan Dewulf, Karuna Adhikari, Christel Vangestel, Tim Van Den Wyngaert and Filipe Elvas

Cancers, 2020, 12, 1868
DOI: 10.3390/cancers12071868