Ksenia Lisova1, Maxim Sergeev2, Susan Evans-Axelsson3, Andreea D Stuparu3, Seval Beykan4, Jeffrey Collins2, Jason Jones1, Michael Lassmann4, Ken Herrmann5, David Perrin6, Jason T Lee7, Roger Slavik8, R Michael van Dam9. 1. Physics in Biology and Medicine Interdepartmental Graduate Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 2. Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 3. Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 4. Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany. 5. Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA. 6. Department of Chemistry, University of British Columbia, Vancouver, BC, Canada. 7. Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA. Electronic address: jasontlee@mednet.ucla.edu. 8. Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA. Electronic address: rslavik@mednet.ucla.edu. 9. Physics in Biology and Medicine Interdepartmental Graduate Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA. Electronic address: mvandam@mednet.ucla.edu.
Abstract
BACKGROUND: Peptides labeled with positron-emitting isotopes are emerging as a versatile class of compounds for the development of highly specific, targeted imaging agents for diagnostic imaging via positron-emission tomography (PET) and for precision medicine via theranostic applications. Despite the success of peptides labeled with gallium-68 (for imaging) or lutetium-177 (for therapy) in the clinical management of patients with neuroendocrine tumors or prostate cancer, there are significant advantages of using fluorine-18 for imaging. Recent developments have greatly simplified such labeling: in particular, labeling of organotrifluoroborates via isotopic exchange can readily be performed in a single-step under aqueous conditions and without the need for HPLC purification. Though an automated synthesis has not yet been explored, microfluidic approaches have emerged for 18F-labeling with high speed, minimal reagents, and high molar activity compared to conventional approaches. As a proof-of-concept, we performed microfluidic labeling of an octreotate analog ([18F]AMBF3-TATE), a promising 18F-labeled analog that could compete with [68Ga]Ga-DOTATATE with the advantage of providing a greater number of patient doses per batch produced. METHODS: Both [18F]AMBF3-TATE and [68Ga]Ga-DOTATATE were labeled, the former by microscale methods adapted from manual labeling, and were imaged in mice bearing human SSTR2-overexpressing, rat SSTR2 wildtype, and SSTR2-negative xenografts. Furthermore, a dosimetry analysis was performed for [18F]AMBF3-TATE. RESULTS: The micro-synthesis exhibited highly-repeatable performance with radiochemical conversion of 50 ± 6% (n = 15), overall decay-corrected radiochemical yield of 16 ± 1% (n = 5) in ~40 min, radiochemical purity >99%, and high molar activity. Preclinical imaging with [18F]AMBF3-TATE in SSTR2 tumor models correlated well with [68Ga]Ga-DOTATATE. The favorable biodistribution, with the highest tracer accumulation in the bladder followed distantly by gastrointestinal tissues, resulted in 1.26 × 10-2 mSv/MBq maximal estimated effective dose in human, a value lower than that reported for current clinical 18F- and 68Ga-labeled compounds. CONCLUSIONS: The combination of novel chemical approaches to 18F-labeling and microdroplet radiochemistry have the potential to serve as a platform for greatly simplified development and production of 18F-labeled peptide tracers. Favorable preclinical imaging and dosimetry of [18F]AMBF3-TATE, combined with a convenient synthesis, validate this assertion and suggest strong potential for clinical translation.
BACKGROUND:Peptides labeled with positron-emitting isotopes are emerging as a versatile class of compounds for the development of highly specific, targeted imaging agents for diagnostic imaging via positron-emission tomography (PET) and for precision medicine via theranostic applications. Despite the success of peptides labeled with gallium-68 (for imaging) or lutetium-177 (for therapy) in the clinical management of patients with neuroendocrine tumors or prostate cancer, there are significant advantages of using fluorine-18 for imaging. Recent developments have greatly simplified such labeling: in particular, labeling of organotrifluoroborates via isotopic exchange can readily be performed in a single-step under aqueous conditions and without the need for HPLC purification. Though an automated synthesis has not yet been explored, microfluidic approaches have emerged for 18F-labeling with high speed, minimal reagents, and high molar activity compared to conventional approaches. As a proof-of-concept, we performed microfluidic labeling of an octreotate analog ([18F]AMBF3-TATE), a promising 18F-labeled analog that could compete with [68Ga]Ga-DOTATATE with the advantage of providing a greater number of patient doses per batch produced. METHODS: Both [18F]AMBF3-TATE and [68Ga]Ga-DOTATATE were labeled, the former by microscale methods adapted from manual labeling, and were imaged in mice bearing humanSSTR2-overexpressing, ratSSTR2 wildtype, and SSTR2-negative xenografts. Furthermore, a dosimetry analysis was performed for [18F]AMBF3-TATE. RESULTS: The micro-synthesis exhibited highly-repeatable performance with radiochemical conversion of 50 ± 6% (n = 15), overall decay-corrected radiochemical yield of 16 ± 1% (n = 5) in ~40 min, radiochemical purity >99%, and high molar activity. Preclinical imaging with [18F]AMBF3-TATE in SSTR2tumor models correlated well with [68Ga]Ga-DOTATATE. The favorable biodistribution, with the highest tracer accumulation in the bladder followed distantly by gastrointestinal tissues, resulted in 1.26 × 10-2 mSv/MBq maximal estimated effective dose in human, a value lower than that reported for current clinical 18F- and 68Ga-labeled compounds. CONCLUSIONS: The combination of novel chemical approaches to 18F-labeling and microdroplet radiochemistry have the potential to serve as a platform for greatly simplified development and production of 18F-labeled peptide tracers. Favorable preclinical imaging and dosimetry of [18F]AMBF3-TATE, combined with a convenient synthesis, validate this assertion and suggest strong potential for clinical translation.
Authors: Pei Yuin Keng; Supin Chen; Huijiang Ding; Saman Sadeghi; Gaurav J Shah; Alex Dooraghi; Michael E Phelps; Nagichettiar Satyamurthy; Arion F Chatziioannou; Chang-Jin Kim; R Michael van Dam Journal: Proc Natl Acad Sci U S A Date: 2011-12-30 Impact factor: 11.205
Authors: Zilin Yu; Hildo J K Ananias; Giuseppe Carlucci; Hilde D Hoving; Wijnand Helfrich; Rudi A J O Dierckx; Fan Wang; Igle J de Jong; Philip H Elsinga Journal: Curr Pharm Des Date: 2013 Impact factor: 3.116
Authors: Thomas Betzel; Cristina Müller; Viola Groehn; Adrienne Müller; Josefine Reber; Cindy R Fischer; Stefanie D Krämer; Roger Schibli; Simon M Ametamey Journal: Bioconjug Chem Date: 2013-01-17 Impact factor: 4.774
Authors: Suraiya R Dubash; Nicholas Keat; Paola Mapelli; Frazer Twyman; Laurence Carroll; Kasia Kozlowski; Adil Al-Nahhas; Azeem Saleem; Mickael Huiban; Ryan Janisch; Andrea Frilling; Rohini Sharma; Eric O Aboagye Journal: J Nucl Med Date: 2016-05-12 Impact factor: 10.057
Authors: Jung Min Chang; Hyun Ju Lee; Jin Mo Goo; Ho-Young Lee; Jong Jin Lee; June-Key Chung; Jung-Gi Im Journal: Korean J Radiol Date: 2006 Jan-Mar Impact factor: 3.500
Authors: Alejandra Rios; Travis S Holloway; Philip H Chao; Christian De Caro; Chelsea C Okoro; R Michael van Dam Journal: Sci Rep Date: 2022-06-17 Impact factor: 4.996
Authors: Mário Ginja; Maria J Pires; José M Gonzalo-Orden; Fernanda Seixas; Miguel Correia-Cardoso; Rita Ferreira; Margarida Fardilha; Paula A Oliveira; Ana I Faustino-Rocha Journal: Diagnostics (Basel) Date: 2019-06-30
Authors: Mohammed Al-Qahtani; Martin Behe; Guy Bormans; Giuseppe Carlucci; Jean Dasilva; Clemens Decristoforo; Philip H Elsinga; Klaus Kopka; Xiang-Guo Li; Robert Mach; Oskar Middel; Jan Passchier; Marianne Patt; Ivan Penuelas; Ana Rey; Peter J H Scott; Sergio Todde; Jun Toyohara; Danielle Vugts Journal: EJNMMI Radiopharm Chem Date: 2021-01-28