Editorial Received 22 February 2014,
Accepted 24 February 2014
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3196
Recent developments in PET and SPECT imaging
J. Label Compd. Radiopharm 2014, 57 191–194
Copyright © 2014 John Wiley & Sons, Ltd.
191
The objective of this Special JLCR volume was to provide a snapshot of current research in molecular imaging with a primary focus on positron emission tomography (PET) and single-photon emission computed tomography (SPECT). We invited contributions from a mix of established figures in the field and those in the early stages of their career for whom this would be their first opportunity to be the sole or main author. We were delighted that virtually all of those invited to contribute were willing to participate. This volume thus comprises 21 articles, some of which are a blend of conventional research papers and reviews, and some of the latter also containing original research. The diversity of topics covered reflects the wide-ranging research in progress in the rapidly expanding field of molecular imaging. To place the work described this volume in context, it might be appropriate to look briefly at some statistics and a comparison of SPECT and PET. Figure 1 presents plots of the number of publications in PET and SPECT imaging indexed by PubMed over the past 30 years. It is only of course a somewhat simplistic representation of the total volume of research in these areas but probably does reflect the levels of activity in the field. The PET line shows virtually exponential growth over this period with no signs of reaching a plateau. By contrast, the publications on SPECT have levelled out at about 26% of current PET imaging papers. The SPECT imaging trend is what one might expect for a mature technique where there is comparatively less innovation. Approximately 40 million radiopharmaceutical-based clinical scans are made annually worldwide. SPECT imaging (mostly via 99mTc) is the dominant technique and accounts for around 95% of scans. The only PET agent that is being used at all widely is FDG, and currently, around one million scans are carried out, although this value is predicted to quadruple over the next couple of years. The driving forces behind the emphasis on PET imaging are higher sensitivity, ease of quantification and the fact that use of 11C or 18F enables the introduction of a radiolabel with minimal structural modification. This is particularly advantageous when labelling small molecules for targeting structurally sensitive targets such as the brain. However, these advantages have to be set against the high capital costs involved in setting up a PET facility, and this suggests that this technique will not be available in the less developed areas of the world in the near future.1 The advantages of PET are perhaps less clear cut for preclinical small animal imaging where the higher sensitivity of PET (around 15 times higher based on phantom imaging) is offset by the higher resolution attainable using SPECT. Even in the clinical setting, there have been detailed comparative studies of PET and SPECT agents in patients with Parkinson’s disease2 or chest lesions,3 which suggest that despite the apparent advantages of PET, the actual diagnostic information obtained using the two techniques are very similar. The very diversity of the contributions in this volume has made it rather difficult to organise them in any simple manner, and the arrangement is inevitably somewhat arbitrary with some overlap between the categories. This is indicated where it occurs. The first group comprises those papers that are focussed on a single radioisotope. The PET isotopes covered range from the well-used 11C and 18 F through the less common 64Cu and 68Ga to the more exotic and perhaps less familiar 13N. In accord with its dominant position in clinical imaging, SPECT radioisotopes are mainly represented by technetium. The volume starts with a review from Smith et al. (paper 1), which surveys the literature from 2007 on palladium-mediated and rhodium-mediated carbonylation with 11CO and includes a detailed discussion of the methods available for pre-trapping of the carbon monoxide. The paper that follows by Kealey et al. (paper 2) focuses on a specific 11CO reaction; the formation of ureas by the palladium-catalysed reaction of 11CO with primary amines using a copper(I) tris(pyrazolylborate) complex to trap the carbon monoxide. The radiochemical yields of urea are in the range 60–100%. The third article by Llop et al. (paper 3) details the very different approach of 11C labelling a carborane using 11CH3I or CH3OTf (OTf = triflate). Carboranes of the type used hereby have been shown to act as analogues of raclopride and are selective for D2 receptor sites in the brain. The particular labelled carborane described in this paper was taken up by D2 receptors, but the accompanying non-specific brain uptake would limit its applicability as an imaging agent. The next two papers offer contrasting approaches to the challenges of radiolabelling with 18F. The first by Betts et al. (paper 4) gives an account of the use of what might be described as a conventional organic chemistry approach to the 18F labelling of pyridines. Reaction of 2,6-dibromopyridine with 18F fluoride gives the 18F-bromopyridine and subsequent metal-catalysed coupling at bromide provides a route to attach appropriate targeting groups. The second paper (paper 5) by Laverman et al. is a review of the group’s pioneering work on the exploitation of the high strength of the Al–F bond to form Al–18F complexes, which are conjugated to biological targeting groups. With judicious selection of the ligand system, the radiolabelling can be carried out in good yields, and conjugation occurs without compromising the binding of the biological vector. The long-lived 64Cu isotope, although less prevalent than 18F and 11C, continues to attract interest, and two papers address different facets of its applications in imaging. The first review by Anderson et al. (paper 6) gives a detailed account of the development and use of the cross-bridged cyclam class of ligand for the formation of highly kinetically stable 64Cu(II) complexes that can be used for PET imaging with minimal loss of radiocopper to naturally occurring sequestering agents in vivo. The review by Hueting (paper 7) presents a different facet of
Editorial
No of publications
7000
PET and SPECT publications per year
6000 5000 4000 PET
3000
SPECT
2000 1000 0 1970 1980 1990 2000 2010 2020
Year Figure 1. Trends in publications in PET and SPECT imaging 1980–2012.
192
the use of radiocopper and gives an overview of the applications of simple 64Cu salts for the imaging of copper metabolism. This is of significance not only in diseases resulting from defects in copper processing but also in other diseases such as cancer. The PET isotope 68Ga is attracting increasing interest largely because it is available via a generator that has a lifetime for clinical imaging of up to a year. A timely mini-review by Archibald et al. (paper 8) covers the range of bifunctional chelators that have been used with 68 Ga and also discusses the labelling conditions that are required. There is a second paper, appearing later in this issue, dealing with 68 Ga by Carroll et al. (paper 16), which focuses on techniques for conjugation and this is referred to in the Methodology section. Lastly, in the PET isotope section, Llop et al. give a comprehensive review of the synthesis and applications of 13N and prospects for the future (paper 9). This isotope has a half-life of only 9.97 min and is generated in a cyclotron by proton irradiation of a 16O target. It can be obtained in moderate yields in a number of different chemical forms, which provide varied labelling strategies. Despite the technical challenges, a wide range of molecules have been labelled, and viable imaging procedures using 13N are emerging. There are four papers covering various aspects of SPECT imaging and/or therapy. Two of these are based on the use of the highly versatile Tc(I) tricarbonyl core developed by Alberto et al. Zubieta et al. (paper 10) present a review of their work on the use of single amino acid chelates bound to a Tc tricarbonyl unit via a tridentate ligand. The amino acid functionality provides an extremely flexible means to attach a wide range of targeting molecules such as N-formyl-methionyl-leucyl-phenylalanine (fMLF) (targets the formyl petide receptor), folic acid and urea-based derivatives for targeting prostate specific membrane antigen. The rhenium analogues are isostructural, and their luminescence can be used to track the behaviour in cells. The Tc/Re tricarbonyl motif has also been exploited in the paper by Donnelly et al. (paper 11), which gives an account of the synthesis and characterisation of both rhenium and technetium tricarbonyl complexes with triazole ligands also bearing a cyclic arginine-glycine-aspartine (RGD) peptide for angiogenesis targeting. Again, the Re complexes are luminescent, permitting the assessment of their cellular distributions to be made. In an interesting review, Braband (paper 12) gives an overview of work aimed at producing a Tc(VII) trioxo core that will be a possible alternative to the well- established tricarbonyl system. While the coordination geometries are notionally similar in the two systems, the trioxo system has the advantage that the oxo groups can react with olefins to give a stable diol ligand, and this reaction has been used to attach a variety of biological targeting compounds. Biological studies with the 99mTc species suggest the conjugates are stable in vivo, and this shows every sign of being a promising approach towards a new class of 99mTc SPECT imaging agents. The final contribution in this range of topics (paper 13) describes the synthesis and potential uses of 177Lu linked to bombesin derivatives for cancer therapy. This isotope is attracting interest as an alternative to 111In for therapeutic applications as it has a half-life of 6.7 days and is a medium-energy β-emitter with accompanying gamma emissions, which can be used for imaging. This contribution by Mindt et al. presents the synthesis of 177Lu–DOTA complexes conjugated to antagonist bombesin analogues and is discussed briefly again later. The next group of papers may be classified under the general heading of ‘methodologies and ligands’, which are, in principle, applicable to a range of radionuclides. Ultrasound is usually associated with imaging, but the review by Blower et al. (paper 14) shows that ultrasound-mediated delivery can significantly improve the delivery and distribution of antibodies or antibody fragments to tumours. The safety of ultrasound and the ability to focus it at prescribed depths render it particularly suitable to augment radiation immune therapy. One of the many challenges of targeting radiolabelled species is to find efficient methods to conjugate appropriate bioactive groups in a site-selective manner under physiological conditions. ‘Click’ chemistry has received much attention chiefly in the form of copper-catalysed addition of azides to alkynes to give stable triazoles. However, this approach is not universally applicable, and alternatives such as the addition of 1,2,4,5-tetrazoles to olefins are being explored. Zeglis et al. (paper 15) review this latter area and give a valuable overview of the underpinning chemistry and provide examples of its use to conjugate radioisotopes to biomolecules. In a complementary paper by Carroll et al. (paper 16), a comparison is made of conjugation of a 68Ga–DOTA derivative to biomolecules. They concluded that while good yields could be obtained by the azide/alkyne route, the tetrazene/olefin worked better in aqueous solution. With the advances in instrumentation, multimodal imaging and in particular PET/MRI is now finding wider use and offers the possibility of combining the high sensitivity of PET with the high resolution of MRI. A mini-review by de Rosales et al. (paper 17) gives a brief survey of PET/MRI and covers the use of gadolinium contrast agents, which are partially labelled with isotopes such as 18F as an alternative to the ‘cocktail’ strategy of using a contrast agent with, say, 18F-FDG. Examples are provided of the use of the bimodal method for measuring tissue pH and imaging of sentinel lymph nodes and thrombi. Lastly, in this section, there is a wide-ranging review by Waghorn (paper 18) on the use of porphyrins as ligands for radiopharmaceuticals. In view of the high stabilities of metalloporphyrins, their fluorescence and their biocompatibility, it is perhaps surprising that they have not been
www.jlcr.org
Copyright © 2014 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2014, 57 191–194
Editorial used more widely. This article summarises both the advantages and disadvantages of this class of ligand for radiopharmaceutical applications and shows that there are imaging applications (such as labelling antibodies) where porphyrins are appropriate. The final selection of articles comes under the very general heading of specific biological targets where the emphasis lies on the biology and labelling required to address specific receptor sites. It opens with a very comprehensive account by Cornelissen (paper 19) of the strategies that can be invoked to target intra cellular epitopes (the functional component of receptors) including ways of traversing cellular and nuclear membranes and localising imaging or therapeutic radionuclides in the nucleus. Many of the major targets currently used in cancer are extracellular, and the focus on processes and targets within the cell offers many new possibilities. Bombesin is a good example of an agent that targets the extracellular gastrin-releasing peptide receptor over-expressed in cancer, and the radiolabelling of antagonist variants with 177Lu is discussed in paper 13 by Mindt et al. The cyclooxygenases COX-1 and COX-2 are expressed in response to inflammatory stimuli such as in cancers. The review by Smith et al. (paper 20) gives a timely synopsis of the current state of research on imaging COX-2 via the radiolabelling with 11C, 18F, 123I and 125I of specific inhibitors. Alzheimer’s disease and dementia are a major and growing challenge to the elderly in certain Western countries, and accurate diagnostic methods are a matter of urgency. The final contribution to this section and to the volume is a very timely and comprehensive review by Holland et al. (paper 21, and cover image of the current issue) of the methods available to diagnose this insidious disease. Not only are methods for imaging amyloid plaque covered, but many more targets and specific inhibitors are discussed. We very much hope that you will enjoy reading these papers as much as the editors have and that you will find them a source of useful information. Hopefully, this volume will help in the dissemination of information amongst the thriving molecular imaging community and provide stimulus for further exciting developments.
References [1] M. Santini, A. Fiorelli, G. Vicidomini, P. Laperuta, L. Busiello, P. Rambaldi, L. Mansi, A. Rotondo, Respiration 2010, 80, 524–533. [2] S. Eshuis, P. Jager, R. Maguire, S. Jonkman, R. Dierckx, K. Leenders, Eur. J. Nucl. Med. Molecular Imaging 2009, 36, 454–462. [3] G. Mariani, L. Bruselli and A. Duatti, Eur.J. Nucl Med Mol Im 2008, 35, 1560–1565.
Sofia Pascu Chemistry Department, University of Bath, Bath, UK [email protected] Jon Dilworth Chemistry Department, University of Oxford, Oxford, UK [email protected]
Contents of volume
J. Label Compd. Radiopharm 2014, 57 191–194
Copyright © 2014 John Wiley & Sons, Ltd.
www.jlcr.org
193
Editorial 1. Recent developments in PET and SPECT imaging ............................................................................................................................................................. 191 S. Pascu and J. Dilworth Chemistry and applications of PET and SPECT radionuclides 2. Transition Metal Mediated [11C] Carbonylation Reactions: Recent Advances and Applications....................................................................195 P. Miller*, S. Kealey, A. Gee 3. Palladium-mediated Oxidative Carbonylation Reactions for the Synthesis of 11C-radiolabelled Ureas......................................................202 S. Kealey*, S. Husbands, I. Bennacef, A. Gee, J. Passchier 4. Synthesis and In Vivo Evaluation of 11C-labeled (1,7-Dicarba-closo-dodecaboran-1-yl)-N-{[(2S)-1-ethylpyrrolidin-2-yl] methyl}amide....................................................................................................................................................................................................................................................209 V. Gomez-Vallejo, N. Vazquez, K. B. Gona, M. Puigivila, M. Gonzalez, E. S. Sebastian, A. Martin, J. Llop* 5. 2-Bromo-6-[18F]fluoropyridine: Two-step Fluorine-18 Radiolabelling Via Transition Metal Mediated Chemistry...................................215 H. M. Betts* and E. G. Robins 6. Al18F Labeling of Peptides and Proteins...................................................................................................................................................................................219 P. Laverman*, W. J. McBride, R. M. Sharkey, D. M. Goldenberg, O. C. Boerman 7. Chelators for Copper Radionuclides in PET Radiopharmaceuticals.............................................................................................................................224 Z. Cai, C. J. Anderson* 8. Radiocopper for the Imaging of Copper Metabolism.........................................................................................................................................................231 R Hueting 9. Recent Advances in Chelator Design and Labelling Methodology for 68Ga Radiopharmaceuticals.............................................................239 S. Archibald*, B. Burke, G. Clemente 10. Nitrogen-13: Historical Review and Future Perspectives................................................................................................................................................244 V. Gomez-Vallego, V. Gaja, K. B. Gona, J. Llop* 11. Single Amino Acid Chelate (SAAC) Complexes of the M(CO)3+ Core for Correlating Fluorescence and Radioimaging Studies (M = 99mTc, Re).......................................................................................................................................................................................255 M. Coogan, R. Doyle, J. Valiant, J. Zubieta* 12. Rhenium and Technetium Tricarbonyl Complexes of 1,4-Substituted pyridyl-1,2,3-triazole Bidentate ‘Click’ Ligands Conjugated to a Targeting RGD Peptide...............................................................................................................................................................262
Editorial P. Donnelly*, T. Connell, D. Hayne, U. Ackerman, H. Tochon-Danguy, J. White 13. High-valent Technetium Chemistry – New Opportunities for Radiopharmaceutical Developments..........................................................270 H. Braband 14. Radiolabeled Antagonistic Bombesin Peptidomimetics for Tumor Targeting.......................................................................................................275 T. Mindt*, I. Valverde, E. Huxol Methodologies and Ligands 15. Prospects for Enhancement of Targeted Radionuclide Therapy of Cancer Using Ultrasound........................................................................279 R. J. Browning, V. Rajkumar, R. B. Pedley, R. J. Eckersley and P. Blower* 16. The Inverse Electron Demand Diels–Alder Click Reaction in Radiochemistry.......................................................................................................285 T. Reiner and B. M. Zeglis* 17. Bioorthogonal Chemistry for 68Ga Radiolabelling of DOTA-containing Compounds.........................................................................................291 H. L. Evans, L. Carroll*, E. G. Aboagye and A. C. Spivey 18. Potential Clinical Applications of Bimodal PET-MR or SPECT-MR Imaging Agents...............................................................................................298 R. T. M. De Rosales 19. Radiolabelled Porphyrins in Nuclear Medicine.....................................................................................................................................................................304 P. J. Waghorn Specific Biological Targets 20. Imaging the Inside of a Tumor: A Review of Radionuclide Imaging and Theranostics Targeting Intracellular Epitopes....................310 B. Cornelissen 21. Imaging COX-2 Expression in Cancer Using PET/SPECT Radioligands: Current Status and Future Directions........................................317 A. Pacelli, J. Greenman, C. Cawthorne and G. Smith* 22. Alternative Approaches for PET Radiotracer Development in Alzheimer’s Disease: Imaging Beyond Plaque.......................................323 J. Holland*, S. Liang, B. Rotstein, L. Collier, I Greguric, N. Vasdev The asterisk denotes the corresponding author.
194 www.jlcr.org
Copyright © 2014 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2014, 57 191–194
Accepted 24 February 2014
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3196
Recent developments in PET and SPECT imaging
J. Label Compd. Radiopharm 2014, 57 191–194
Copyright © 2014 John Wiley & Sons, Ltd.
191
The objective of this Special JLCR volume was to provide a snapshot of current research in molecular imaging with a primary focus on positron emission tomography (PET) and single-photon emission computed tomography (SPECT). We invited contributions from a mix of established figures in the field and those in the early stages of their career for whom this would be their first opportunity to be the sole or main author. We were delighted that virtually all of those invited to contribute were willing to participate. This volume thus comprises 21 articles, some of which are a blend of conventional research papers and reviews, and some of the latter also containing original research. The diversity of topics covered reflects the wide-ranging research in progress in the rapidly expanding field of molecular imaging. To place the work described this volume in context, it might be appropriate to look briefly at some statistics and a comparison of SPECT and PET. Figure 1 presents plots of the number of publications in PET and SPECT imaging indexed by PubMed over the past 30 years. It is only of course a somewhat simplistic representation of the total volume of research in these areas but probably does reflect the levels of activity in the field. The PET line shows virtually exponential growth over this period with no signs of reaching a plateau. By contrast, the publications on SPECT have levelled out at about 26% of current PET imaging papers. The SPECT imaging trend is what one might expect for a mature technique where there is comparatively less innovation. Approximately 40 million radiopharmaceutical-based clinical scans are made annually worldwide. SPECT imaging (mostly via 99mTc) is the dominant technique and accounts for around 95% of scans. The only PET agent that is being used at all widely is FDG, and currently, around one million scans are carried out, although this value is predicted to quadruple over the next couple of years. The driving forces behind the emphasis on PET imaging are higher sensitivity, ease of quantification and the fact that use of 11C or 18F enables the introduction of a radiolabel with minimal structural modification. This is particularly advantageous when labelling small molecules for targeting structurally sensitive targets such as the brain. However, these advantages have to be set against the high capital costs involved in setting up a PET facility, and this suggests that this technique will not be available in the less developed areas of the world in the near future.1 The advantages of PET are perhaps less clear cut for preclinical small animal imaging where the higher sensitivity of PET (around 15 times higher based on phantom imaging) is offset by the higher resolution attainable using SPECT. Even in the clinical setting, there have been detailed comparative studies of PET and SPECT agents in patients with Parkinson’s disease2 or chest lesions,3 which suggest that despite the apparent advantages of PET, the actual diagnostic information obtained using the two techniques are very similar. The very diversity of the contributions in this volume has made it rather difficult to organise them in any simple manner, and the arrangement is inevitably somewhat arbitrary with some overlap between the categories. This is indicated where it occurs. The first group comprises those papers that are focussed on a single radioisotope. The PET isotopes covered range from the well-used 11C and 18 F through the less common 64Cu and 68Ga to the more exotic and perhaps less familiar 13N. In accord with its dominant position in clinical imaging, SPECT radioisotopes are mainly represented by technetium. The volume starts with a review from Smith et al. (paper 1), which surveys the literature from 2007 on palladium-mediated and rhodium-mediated carbonylation with 11CO and includes a detailed discussion of the methods available for pre-trapping of the carbon monoxide. The paper that follows by Kealey et al. (paper 2) focuses on a specific 11CO reaction; the formation of ureas by the palladium-catalysed reaction of 11CO with primary amines using a copper(I) tris(pyrazolylborate) complex to trap the carbon monoxide. The radiochemical yields of urea are in the range 60–100%. The third article by Llop et al. (paper 3) details the very different approach of 11C labelling a carborane using 11CH3I or CH3OTf (OTf = triflate). Carboranes of the type used hereby have been shown to act as analogues of raclopride and are selective for D2 receptor sites in the brain. The particular labelled carborane described in this paper was taken up by D2 receptors, but the accompanying non-specific brain uptake would limit its applicability as an imaging agent. The next two papers offer contrasting approaches to the challenges of radiolabelling with 18F. The first by Betts et al. (paper 4) gives an account of the use of what might be described as a conventional organic chemistry approach to the 18F labelling of pyridines. Reaction of 2,6-dibromopyridine with 18F fluoride gives the 18F-bromopyridine and subsequent metal-catalysed coupling at bromide provides a route to attach appropriate targeting groups. The second paper (paper 5) by Laverman et al. is a review of the group’s pioneering work on the exploitation of the high strength of the Al–F bond to form Al–18F complexes, which are conjugated to biological targeting groups. With judicious selection of the ligand system, the radiolabelling can be carried out in good yields, and conjugation occurs without compromising the binding of the biological vector. The long-lived 64Cu isotope, although less prevalent than 18F and 11C, continues to attract interest, and two papers address different facets of its applications in imaging. The first review by Anderson et al. (paper 6) gives a detailed account of the development and use of the cross-bridged cyclam class of ligand for the formation of highly kinetically stable 64Cu(II) complexes that can be used for PET imaging with minimal loss of radiocopper to naturally occurring sequestering agents in vivo. The review by Hueting (paper 7) presents a different facet of
Editorial
No of publications
7000
PET and SPECT publications per year
6000 5000 4000 PET
3000
SPECT
2000 1000 0 1970 1980 1990 2000 2010 2020
Year Figure 1. Trends in publications in PET and SPECT imaging 1980–2012.
192
the use of radiocopper and gives an overview of the applications of simple 64Cu salts for the imaging of copper metabolism. This is of significance not only in diseases resulting from defects in copper processing but also in other diseases such as cancer. The PET isotope 68Ga is attracting increasing interest largely because it is available via a generator that has a lifetime for clinical imaging of up to a year. A timely mini-review by Archibald et al. (paper 8) covers the range of bifunctional chelators that have been used with 68 Ga and also discusses the labelling conditions that are required. There is a second paper, appearing later in this issue, dealing with 68 Ga by Carroll et al. (paper 16), which focuses on techniques for conjugation and this is referred to in the Methodology section. Lastly, in the PET isotope section, Llop et al. give a comprehensive review of the synthesis and applications of 13N and prospects for the future (paper 9). This isotope has a half-life of only 9.97 min and is generated in a cyclotron by proton irradiation of a 16O target. It can be obtained in moderate yields in a number of different chemical forms, which provide varied labelling strategies. Despite the technical challenges, a wide range of molecules have been labelled, and viable imaging procedures using 13N are emerging. There are four papers covering various aspects of SPECT imaging and/or therapy. Two of these are based on the use of the highly versatile Tc(I) tricarbonyl core developed by Alberto et al. Zubieta et al. (paper 10) present a review of their work on the use of single amino acid chelates bound to a Tc tricarbonyl unit via a tridentate ligand. The amino acid functionality provides an extremely flexible means to attach a wide range of targeting molecules such as N-formyl-methionyl-leucyl-phenylalanine (fMLF) (targets the formyl petide receptor), folic acid and urea-based derivatives for targeting prostate specific membrane antigen. The rhenium analogues are isostructural, and their luminescence can be used to track the behaviour in cells. The Tc/Re tricarbonyl motif has also been exploited in the paper by Donnelly et al. (paper 11), which gives an account of the synthesis and characterisation of both rhenium and technetium tricarbonyl complexes with triazole ligands also bearing a cyclic arginine-glycine-aspartine (RGD) peptide for angiogenesis targeting. Again, the Re complexes are luminescent, permitting the assessment of their cellular distributions to be made. In an interesting review, Braband (paper 12) gives an overview of work aimed at producing a Tc(VII) trioxo core that will be a possible alternative to the well- established tricarbonyl system. While the coordination geometries are notionally similar in the two systems, the trioxo system has the advantage that the oxo groups can react with olefins to give a stable diol ligand, and this reaction has been used to attach a variety of biological targeting compounds. Biological studies with the 99mTc species suggest the conjugates are stable in vivo, and this shows every sign of being a promising approach towards a new class of 99mTc SPECT imaging agents. The final contribution in this range of topics (paper 13) describes the synthesis and potential uses of 177Lu linked to bombesin derivatives for cancer therapy. This isotope is attracting interest as an alternative to 111In for therapeutic applications as it has a half-life of 6.7 days and is a medium-energy β-emitter with accompanying gamma emissions, which can be used for imaging. This contribution by Mindt et al. presents the synthesis of 177Lu–DOTA complexes conjugated to antagonist bombesin analogues and is discussed briefly again later. The next group of papers may be classified under the general heading of ‘methodologies and ligands’, which are, in principle, applicable to a range of radionuclides. Ultrasound is usually associated with imaging, but the review by Blower et al. (paper 14) shows that ultrasound-mediated delivery can significantly improve the delivery and distribution of antibodies or antibody fragments to tumours. The safety of ultrasound and the ability to focus it at prescribed depths render it particularly suitable to augment radiation immune therapy. One of the many challenges of targeting radiolabelled species is to find efficient methods to conjugate appropriate bioactive groups in a site-selective manner under physiological conditions. ‘Click’ chemistry has received much attention chiefly in the form of copper-catalysed addition of azides to alkynes to give stable triazoles. However, this approach is not universally applicable, and alternatives such as the addition of 1,2,4,5-tetrazoles to olefins are being explored. Zeglis et al. (paper 15) review this latter area and give a valuable overview of the underpinning chemistry and provide examples of its use to conjugate radioisotopes to biomolecules. In a complementary paper by Carroll et al. (paper 16), a comparison is made of conjugation of a 68Ga–DOTA derivative to biomolecules. They concluded that while good yields could be obtained by the azide/alkyne route, the tetrazene/olefin worked better in aqueous solution. With the advances in instrumentation, multimodal imaging and in particular PET/MRI is now finding wider use and offers the possibility of combining the high sensitivity of PET with the high resolution of MRI. A mini-review by de Rosales et al. (paper 17) gives a brief survey of PET/MRI and covers the use of gadolinium contrast agents, which are partially labelled with isotopes such as 18F as an alternative to the ‘cocktail’ strategy of using a contrast agent with, say, 18F-FDG. Examples are provided of the use of the bimodal method for measuring tissue pH and imaging of sentinel lymph nodes and thrombi. Lastly, in this section, there is a wide-ranging review by Waghorn (paper 18) on the use of porphyrins as ligands for radiopharmaceuticals. In view of the high stabilities of metalloporphyrins, their fluorescence and their biocompatibility, it is perhaps surprising that they have not been
www.jlcr.org
Copyright © 2014 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2014, 57 191–194
Editorial used more widely. This article summarises both the advantages and disadvantages of this class of ligand for radiopharmaceutical applications and shows that there are imaging applications (such as labelling antibodies) where porphyrins are appropriate. The final selection of articles comes under the very general heading of specific biological targets where the emphasis lies on the biology and labelling required to address specific receptor sites. It opens with a very comprehensive account by Cornelissen (paper 19) of the strategies that can be invoked to target intra cellular epitopes (the functional component of receptors) including ways of traversing cellular and nuclear membranes and localising imaging or therapeutic radionuclides in the nucleus. Many of the major targets currently used in cancer are extracellular, and the focus on processes and targets within the cell offers many new possibilities. Bombesin is a good example of an agent that targets the extracellular gastrin-releasing peptide receptor over-expressed in cancer, and the radiolabelling of antagonist variants with 177Lu is discussed in paper 13 by Mindt et al. The cyclooxygenases COX-1 and COX-2 are expressed in response to inflammatory stimuli such as in cancers. The review by Smith et al. (paper 20) gives a timely synopsis of the current state of research on imaging COX-2 via the radiolabelling with 11C, 18F, 123I and 125I of specific inhibitors. Alzheimer’s disease and dementia are a major and growing challenge to the elderly in certain Western countries, and accurate diagnostic methods are a matter of urgency. The final contribution to this section and to the volume is a very timely and comprehensive review by Holland et al. (paper 21, and cover image of the current issue) of the methods available to diagnose this insidious disease. Not only are methods for imaging amyloid plaque covered, but many more targets and specific inhibitors are discussed. We very much hope that you will enjoy reading these papers as much as the editors have and that you will find them a source of useful information. Hopefully, this volume will help in the dissemination of information amongst the thriving molecular imaging community and provide stimulus for further exciting developments.
References [1] M. Santini, A. Fiorelli, G. Vicidomini, P. Laperuta, L. Busiello, P. Rambaldi, L. Mansi, A. Rotondo, Respiration 2010, 80, 524–533. [2] S. Eshuis, P. Jager, R. Maguire, S. Jonkman, R. Dierckx, K. Leenders, Eur. J. Nucl. Med. Molecular Imaging 2009, 36, 454–462. [3] G. Mariani, L. Bruselli and A. Duatti, Eur.J. Nucl Med Mol Im 2008, 35, 1560–1565.
Sofia Pascu Chemistry Department, University of Bath, Bath, UK [email protected] Jon Dilworth Chemistry Department, University of Oxford, Oxford, UK [email protected]
Contents of volume
J. Label Compd. Radiopharm 2014, 57 191–194
Copyright © 2014 John Wiley & Sons, Ltd.
www.jlcr.org
193
Editorial 1. Recent developments in PET and SPECT imaging ............................................................................................................................................................. 191 S. Pascu and J. Dilworth Chemistry and applications of PET and SPECT radionuclides 2. Transition Metal Mediated [11C] Carbonylation Reactions: Recent Advances and Applications....................................................................195 P. Miller*, S. Kealey, A. Gee 3. Palladium-mediated Oxidative Carbonylation Reactions for the Synthesis of 11C-radiolabelled Ureas......................................................202 S. Kealey*, S. Husbands, I. Bennacef, A. Gee, J. Passchier 4. Synthesis and In Vivo Evaluation of 11C-labeled (1,7-Dicarba-closo-dodecaboran-1-yl)-N-{[(2S)-1-ethylpyrrolidin-2-yl] methyl}amide....................................................................................................................................................................................................................................................209 V. Gomez-Vallejo, N. Vazquez, K. B. Gona, M. Puigivila, M. Gonzalez, E. S. Sebastian, A. Martin, J. Llop* 5. 2-Bromo-6-[18F]fluoropyridine: Two-step Fluorine-18 Radiolabelling Via Transition Metal Mediated Chemistry...................................215 H. M. Betts* and E. G. Robins 6. Al18F Labeling of Peptides and Proteins...................................................................................................................................................................................219 P. Laverman*, W. J. McBride, R. M. Sharkey, D. M. Goldenberg, O. C. Boerman 7. Chelators for Copper Radionuclides in PET Radiopharmaceuticals.............................................................................................................................224 Z. Cai, C. J. Anderson* 8. Radiocopper for the Imaging of Copper Metabolism.........................................................................................................................................................231 R Hueting 9. Recent Advances in Chelator Design and Labelling Methodology for 68Ga Radiopharmaceuticals.............................................................239 S. Archibald*, B. Burke, G. Clemente 10. Nitrogen-13: Historical Review and Future Perspectives................................................................................................................................................244 V. Gomez-Vallego, V. Gaja, K. B. Gona, J. Llop* 11. Single Amino Acid Chelate (SAAC) Complexes of the M(CO)3+ Core for Correlating Fluorescence and Radioimaging Studies (M = 99mTc, Re).......................................................................................................................................................................................255 M. Coogan, R. Doyle, J. Valiant, J. Zubieta* 12. Rhenium and Technetium Tricarbonyl Complexes of 1,4-Substituted pyridyl-1,2,3-triazole Bidentate ‘Click’ Ligands Conjugated to a Targeting RGD Peptide...............................................................................................................................................................262
Editorial P. Donnelly*, T. Connell, D. Hayne, U. Ackerman, H. Tochon-Danguy, J. White 13. High-valent Technetium Chemistry – New Opportunities for Radiopharmaceutical Developments..........................................................270 H. Braband 14. Radiolabeled Antagonistic Bombesin Peptidomimetics for Tumor Targeting.......................................................................................................275 T. Mindt*, I. Valverde, E. Huxol Methodologies and Ligands 15. Prospects for Enhancement of Targeted Radionuclide Therapy of Cancer Using Ultrasound........................................................................279 R. J. Browning, V. Rajkumar, R. B. Pedley, R. J. Eckersley and P. Blower* 16. The Inverse Electron Demand Diels–Alder Click Reaction in Radiochemistry.......................................................................................................285 T. Reiner and B. M. Zeglis* 17. Bioorthogonal Chemistry for 68Ga Radiolabelling of DOTA-containing Compounds.........................................................................................291 H. L. Evans, L. Carroll*, E. G. Aboagye and A. C. Spivey 18. Potential Clinical Applications of Bimodal PET-MR or SPECT-MR Imaging Agents...............................................................................................298 R. T. M. De Rosales 19. Radiolabelled Porphyrins in Nuclear Medicine.....................................................................................................................................................................304 P. J. Waghorn Specific Biological Targets 20. Imaging the Inside of a Tumor: A Review of Radionuclide Imaging and Theranostics Targeting Intracellular Epitopes....................310 B. Cornelissen 21. Imaging COX-2 Expression in Cancer Using PET/SPECT Radioligands: Current Status and Future Directions........................................317 A. Pacelli, J. Greenman, C. Cawthorne and G. Smith* 22. Alternative Approaches for PET Radiotracer Development in Alzheimer’s Disease: Imaging Beyond Plaque.......................................323 J. Holland*, S. Liang, B. Rotstein, L. Collier, I Greguric, N. Vasdev The asterisk denotes the corresponding author.
194 www.jlcr.org
Copyright © 2014 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2014, 57 191–194
