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      High-Efficiency Production of Radiopharmaceuticals via Droplet Radiochemistry: A Review of Recent Progress

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          Abstract

          New platforms are enabling radiochemistry to be carried out in tiny, microliter-scale volumes, and this capability has enormous benefits for the production of radiopharmaceuticals. These droplet-based technologies can achieve comparable or better yields compared to conventional methods, but with vastly reduced reagent consumption, shorter synthesis time, higher molar activity (even for low activity batches), faster purification, and ultra-compact system size. We review here the state of the art of this emerging direction, summarize the radiotracers and prosthetic groups that have been synthesized in droplet format, describe recent achievements in scaling up activity levels, and discuss advantages and limitations and the future outlook of these innovative devices.

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          Positron emission tomography provides molecular imaging of biological processes.

          M Phelps (2000)
          Diseases are biological processes, and molecular imaging with positron emission tomography (PET) is sensitive to and informative of these processes. This is illustrated by detection of biological abnormalities in neurological disorders with no computed tomography or MRI anatomic changes, as well as even before symptoms are expressed. PET whole body imaging in cancer provides the means to (i) identify early disease, (ii) differentiate benign from malignant lesions, (iii) examine all organs for metastases, and (iv) determine therapeutic effectiveness. Diagnostic accuracy of PET is 8-43% higher than conventional procedures and changes treatment in 20-40% of the patients, depending on the clinical question, in lung and colorectal cancers, melanoma, and lymphoma, with similar findings in breast, ovarian, head and neck, and renal cancers. A microPET scanner for mice, in concert with human PET systems, provides a novel technology for molecular imaging assays of metabolism and signal transduction to gene expression, from mice to patients: e.g., PET reporter gene assays are used to trace the location and temporal level of expression of therapeutic and endogenous genes. PET probes and drugs are being developed together-in low mass amounts, as molecular imaging probes to image the function of targets without disturbing them, and in mass amounts to modify the target's function as a drug. Molecular imaging by PET, optical technologies, magnetic resonance imaging, single photon emission tomography, and other technologies are assisting in moving research findings from in vitro biology to in vivo integrative mammalian biology of disease.
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            The Use of 18F-FDG-PET/CT for Diagnosis and Treatment Monitoring of Inflammatory and Infectious Diseases

            Andor W. J. M. Glaudemans, Erik F. J. de Vries, Filippo Galli … (2013)
            FDG-PET, combined with CT, is nowadays getting more and more relevant for the diagnosis of several infectious and inflammatory diseases and particularly for therapy monitoring. Thus, this paper gives special attention to the role of FDG-PET/CT in the diagnosis and therapy monitoring of infectious and inflammatory diseases. Enough evidence in the literature already exists about the usefulness of FDG-PET/CT in the diagnosis, management, and followup of patients with sarcoidosis, spondylodiscitis, and vasculitis. For other diseases, such as inflammatory bowel diseases, rheumatoid arthritis, autoimmune pancreatitis, and fungal infections, hard evidence is lacking, but studies also point out that FDG-PET/CT could be useful. It is of invaluable importance to have large prospective multicenter studies in this field to provide clear answers, not only for the status of nuclear medicine in general but also to reduce high costs of treatment.
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              Multistep synthesis of a radiolabeled imaging probe using integrated microfluidics.

              Arkadij M. Elizarov, Hyoung-Shik Shin, Chengyi Shu … (2005)
              Microreactor technology has shown potential for optimizing synthetic efficiency, particularly in preparing sensitive compounds. We achieved the synthesis of an [(18)F]fluoride-radiolabeled molecular imaging probe, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), in an integrated microfluidic device. Five sequential processes-[18F]fluoride concentration, water evaporation, radiofluorination, solvent exchange, and hydrolytic deprotection-proceeded with high radio-chemical yield and purity and with shorter synthesis time relative to conventional automated synthesis. Multiple doses of [18F]FDG for positron emission tomography imaging studies in mice were prepared. These results, which constitute a proof of principle for automated multistep syntheses at the nanogram to microgram scale, could be generalized to a range of radiolabeled substrates.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Imaging
                Journal ID (iso-abbrev): Mol Imaging
                Journal ID (publisher-id): MIX
                Journal ID (hwp): spmix
                Title: Molecular Imaging
                Publisher: SAGE Publications (Sage CA: Los Angeles, CA )
                ISSN (Print): 1535-3508
                ISSN (Electronic): 1536-0121
                Publication date (Electronic): 9 December 2020
                Publication date Collection: Jan-Dec 2020
                Volume: 19
                Electronic Location Identifier: 1536012120973099
                Affiliations
                [1 ]Crump Institute for Molecular Imaging and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA, Los Angeles, CA, USA
                Author notes
                [*]R. Michael van Dam, UCLA Crump Institute for Molecular Imaging 570 Westwood Plaza, Los Angeles, CA 90095, USA. Email: mvandam@ 123456mednet.ucla.edu
                Author information
                https://orcid.org/0000-0002-0070-1320
                https://orcid.org/0000-0003-2316-0173
                Article
                Publisher ID: 10.1177_1536012120973099
                DOI: 10.1177/1536012120973099
                PMC ID: 7731702
                PubMed ID: 33296272
                SO-VID: 9458e095-220e-4550-b038-aef108a25e6e
                Copyright © © SAGE Publications Inc. 2020
                License:

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 16 June 2020
                Date revision received : 02 September 2020
                Date accepted : 12 October 2020
                Funding
                Funded by: National Cancer Institute, FundRef https://doi.org/10.13039/100000054;
                Award ID: R33 CA240201
                Categories
                Subject: Review Article
                Custom metadata
                cover-date January-December 2020
                typesetter ts3

                Keywords: advances in pet/spect probes,novel chemistry methods and approaches,lab-on-a-chip devices,pet,radiochemistry
                Data availability:
                Keywords: advances in pet/spect probes, novel chemistry methods and approaches, lab-on-a-chip devices, pet, radiochemistry

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