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21 pages, 3828 KiB

Open AccessArticle

Development of Novel Analogs of the Monocarboxylate Transporter Ligand FACH and Biological Validation of One Potential Radiotracer for Positron Emission Tomography (PET) Imaging

by Masoud Sadeghzadeh, Barbara Wenzel, Daniel Gündel, Winnie Deuther-Conrad, Magali Toussaint, Rareş-Petru Moldovan, Steffen Fischer, Friedrich-Alexander Ludwig, Rodrigo Teodoro, Shirisha Jonnalagadda, Sravan K. Jonnalagadda, Gerrit Schüürmann, Venkatram R. Mereddy, Lester R. Drewes and Peter Brust

Molecules 2020, 25(10), 2309; https://doi.org/10.3390/molecules25102309 - 14 May 2020

Cited by 5 | Viewed by 3483

Abstract

Monocarboxylate transporters 1-4 (MCT1-4) are involved in several metabolism-related diseases, especially cancer, providing the chance to be considered as relevant targets for diagnosis and therapy. [¹⁸F]FACH was recently developed and showed very promising preclinical results as a potential positron emission tomography [...] Read more.

Monocarboxylate transporters 1-4 (MCT1-4) are involved in several metabolism-related diseases, especially cancer, providing the chance to be considered as relevant targets for diagnosis and therapy. [¹⁸F]FACH was recently developed and showed very promising preclinical results as a potential positron emission tomography (PET) radiotracer for imaging of MCTs. Given that [¹⁸F]FACH did not show high blood-brain barrier permeability, the current work is aimed to investigate whether more lipophilic analogs of FACH could improve brain uptake for imaging of gliomas, while retaining binding to MCTs. The 2-fluoropyridinyl-substituted analogs 1 and 2 were synthesized and their MCT1 inhibition was estimated by [¹⁴C]lactate uptake assay on rat brain endothelial-4 (RBE4) cells. While compounds 1 and 2 showed lower MCT1 inhibitory potencies than FACH (IC₅₀ = 11 nM) by factors of 11 and 25, respectively, 1 (IC₅₀ = 118 nM) could still be a suitable PET candidate. Therefore, 1 was selected for radiosynthesis of [¹⁸F]1 and subsequent biological evaluation for imaging of the MCT expression in mouse brain. Regarding lipophilicity, the experimental log D_7.4 result for [¹⁸F]1 agrees pretty well with its predicted value. In vivo and in vitro studies revealed high uptake of the new radiotracer in kidney and other peripheral MCT-expressing organs together with significant reduction by using specific MCT1 inhibitor α-cyano-4-hydroxycinnamic acid. Despite a higher lipophilicity of [¹⁸F]1 compared to [¹⁸F]FACH, the in vivo brain uptake of [¹⁸F]1 was in a similar range, which is reflected by calculated BBB permeabilities as well through similar transport rates by MCTs on RBE4 cells. Further investigation is needed to clarify the MCT-mediated transport mechanism of these radiotracers in brain. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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17 pages, 2449 KiB

Open AccessArticle

Sigma-1 Receptor Positron Emission Tomography: A New Molecular Imaging Approach Using (S)-(−)-[¹⁸F]Fluspidine in Glioblastoma

by Magali Toussaint, Winnie Deuther-Conrad, Mathias Kranz, Steffen Fischer, Friedrich-Alexander Ludwig, Tareq A. Juratli, Marianne Patt, Bernhard Wünsch, Gabriele Schackert, Osama Sabri and Peter Brust

Molecules 2020, 25(9), 2170; https://doi.org/10.3390/molecules25092170 - 6 May 2020

Cited by 6 | Viewed by 4081

Abstract

Glioblastoma multiforme (GBM) is the most devastating primary brain tumour characterised by infiltrative growth and resistance to therapies. According to recent research, the sigma-1 receptor (sig1R), an endoplasmic reticulum chaperone protein, is involved in signaling pathways assumed to control the proliferation of cancer [...] Read more.

Glioblastoma multiforme (GBM) is the most devastating primary brain tumour characterised by infiltrative growth and resistance to therapies. According to recent research, the sigma-1 receptor (sig1R), an endoplasmic reticulum chaperone protein, is involved in signaling pathways assumed to control the proliferation of cancer cells and thus could serve as candidate for molecular characterisation of GBM. To test this hypothesis, we used the clinically applied sig1R-ligand (S)-(−)-[¹⁸F]fluspidine in imaging studies in an orthotopic mouse model of GBM (U87-MG) as well as in human GBM tissue. A tumour-specific overexpression of sig1R in the U87-MG model was revealed in vitro by autoradiography. The binding parameters demonstrated target-selective binding according to identical K_D values in the tumour area and the contralateral side, but a higher density of sig1R in the tumour. Different kinetic profiles were observed in both areas, with a slower washout in the tumour tissue compared to the contralateral side. The translational relevance of sig1R imaging in oncology is reflected by the autoradiographic detection of tumour-specific expression of sig1R in samples obtained from patients with glioblastoma. Thus, the herein presented data support further research on sig1R in neuro-oncology. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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12 pages, 3514 KiB

Open AccessArticle

Preclinical Incorporation Dosimetry of [¹⁸F]FACH—A Novel ¹⁸F-Labeled MCT1/MCT4 Lactate Transporter Inhibitor for Imaging Cancer Metabolism with PET

by Bernhard Sattler, Mathias Kranz, Barbara Wenzel, Nalin T. Jain, Rareş-Petru Moldovan, Magali Toussaint, Winnie Deuther-Conrad, Friedrich-Alexander Ludwig, Rodrigo Teodoro, Tatjana Sattler, Masoud Sadeghzadeh, Osama Sabri and Peter Brust

Molecules 2020, 25(9), 2024; https://doi.org/10.3390/molecules25092024 - 26 Apr 2020

Cited by 3 | Viewed by 3726

Abstract

Overexpression of monocarboxylate transporters (MCTs) has been shown for a variety of human cancers (e.g., colon, brain, breast, and kidney) and inhibition resulted in intracellular lactate accumulation, acidosis, and cell death. Thus, MCTs are promising targets to investigate tumor cancer metabolism with positron [...] Read more.

Overexpression of monocarboxylate transporters (MCTs) has been shown for a variety of human cancers (e.g., colon, brain, breast, and kidney) and inhibition resulted in intracellular lactate accumulation, acidosis, and cell death. Thus, MCTs are promising targets to investigate tumor cancer metabolism with positron emission tomography (PET). Here, the organ doses (ODs) and the effective dose (ED) of the first ¹⁸F-labeled MCT1/MCT4 inhibitor were estimated in juvenile pigs. Whole-body dosimetry was performed in three piglets (age: ~6 weeks, weight: ~13–15 kg). The animals were anesthetized and subjected to sequential hybrid Positron Emission Tomography and Computed Tomography (PET/CT) up to 5 h after an intravenous (iv) injection of 156 ± 54 MBq [¹⁸F]FACH. All relevant organs were defined by volumes of interest. Exponential curves were fitted to the time–activity data. Time and mass scales were adapted to the human order of magnitude and the ODs calculated using the ICRP 89 adult male phantom with OLINDA 2.1. The ED was calculated using tissue weighting factors as published in Publication 103 of the International Commission of Radiation Protection (ICRP103). The highest organ dose was received by the urinary bladder (62.6 ± 28.9 µSv/MBq), followed by the gall bladder (50.4 ± 37.5 µSv/MBq) and the pancreas (30.5 ± 27.3 µSv/MBq). The highest contribution to the ED was by the urinary bladder (2.5 ± 1.1 µSv/MBq), followed by the red marrow (1.7 ± 0.3 µSv/MBq) and the stomach (1.3 ± 0.4 µSv/MBq). According to this preclinical analysis, the ED to humans is 12.4 µSv/MBq when applying the ICRP103 tissue weighting factors. Taking into account that preclinical dosimetry underestimates the dose to humans by up to 40%, the conversion factor applied for estimation of the ED to humans would rise to 20.6 µSv/MBq. In this case, the ED to humans upon an iv application of ~300 MBq [¹⁸F]FACH would be about 6.2 mSv. This risk assessment encourages the translation of [¹⁸F]FACH into clinical study phases and the further investigation of its potential as a clinical tool for cancer imaging with PET. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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10 pages, 4269 KiB

Open AccessArticle

Improved Detection of Molecular Markers of Atherosclerotic Plaques Using Sub-Millimeter PET Imaging

by Jessica Bridoux, Sara Neyt, Pieterjan Debie, Benedicte Descamps, Nick Devoogdt, Frederik Cleeren, Guy Bormans, Alexis Broisat, Vicky Caveliers, Catarina Xavier, Christian Vanhove and Sophie Hernot

Molecules 2020, 25(8), 1838; https://doi.org/10.3390/molecules25081838 - 16 Apr 2020

Cited by 13 | Viewed by 3374

Abstract

Since atherosclerotic plaques are small and sparse, their non-invasive detection via PET imaging requires both highly specific radiotracers as well as imaging systems with high sensitivity and resolution. This study aimed to assess the targeting and biodistribution of a novel fluorine-18 anti-VCAM-1 Nanobody [...] Read more.

Since atherosclerotic plaques are small and sparse, their non-invasive detection via PET imaging requires both highly specific radiotracers as well as imaging systems with high sensitivity and resolution. This study aimed to assess the targeting and biodistribution of a novel fluorine-18 anti-VCAM-1 Nanobody (Nb), and to investigate whether sub-millimetre resolution PET imaging could improve detectability of plaques in mice. The anti-VCAM-1 Nb functionalised with the novel restrained complexing agent (RESCA) chelator was labelled with [¹⁸F]AlF with a high radiochemical yield (>75%) and radiochemical purity (>99%). Subsequently, [¹⁸F]AlF(RESCA)-cAbVCAM1-5 was injected in ApoE^−/− mice, or co-injected with excess of unlabelled Nb (control group). Mice were imaged sequentially using a cross-over design on two different commercially available PET/CT systems and finally sacrificed for ex vivo analysis. Both the PET/CT images and ex vivo data showed specific uptake of [¹⁸F]AlF(RESCA)-cAbVCAM1-5 in atherosclerotic lesions. Non-specific bone uptake was also noticeable, most probably due to in vivo defluorination. Image analysis yielded higher target-to-heart and target-to-brain ratios with the β-CUBE (MOLECUBES) PET scanner, demonstrating that preclinical detection of atherosclerotic lesions could be improved using the latest PET technology. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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12 pages, 2373 KiB

Open AccessArticle

Thiol-Reactive PODS-Bearing Bifunctional Chelators for the Development of EGFR-Targeting [¹⁸F]AlF-Affibody Conjugates

by Chiara Da Pieve, Ata Makarem, Stephen Turnock, Justyna Maczynska, Graham Smith and Gabriela Kramer-Marek

Molecules 2020, 25(7), 1562; https://doi.org/10.3390/molecules25071562 - 29 Mar 2020

Cited by 15 | Viewed by 4422

Abstract

Site-selective bioconjugation of cysteine-containing peptides and proteins is currently achieved via a maleimide–thiol reaction (Michael addition). When maleimide-functionalized chelators are used and the resulting bioconjugates are subsequently radiolabeled, instability has been observed both during radiosynthesis and post-injection in vivo, reducing radiochemical yield and [...] Read more.

Site-selective bioconjugation of cysteine-containing peptides and proteins is currently achieved via a maleimide–thiol reaction (Michael addition). When maleimide-functionalized chelators are used and the resulting bioconjugates are subsequently radiolabeled, instability has been observed both during radiosynthesis and post-injection in vivo, reducing radiochemical yield and negatively impacting performance. Recently, a phenyloxadiazolyl methylsulfone derivative (PODS) was proposed as an alternative to maleimide for the site-selective conjugation and radiolabeling of proteins, demonstrating improved in vitro stability and in vivo performance. Therefore, we have synthesized two novel PODS-bearing bifunctional chelators (NOTA-PODS and NODAGA-PODS) and attached them to the EGFR-targeting affibody molecule Z_EGFR:03115. After radiolabeling with the aluminum fluoride complex ([¹⁸F]AlF), both conjugates showed good stability in murine serum. When injected in high EGFR-expressing tumor-bearing mice, [¹⁸F]AlF-NOTA-PODS-Z_EGFR:03115 and [¹⁸F]AlF-NODAGA-PODS-Z_EGFR:03115 showed similar pharmacokinetics and a specific tumor uptake of 14.1 ± 5.3% and 16.7 ± 4.5% ID/g at 1 h post-injection, respectively. The current results are encouraging for using PODS as an alternative to maleimide-based thiol-selective bioconjugation reactions. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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9 pages, 1938 KiB

Open AccessArticle

The Effects of Intramuscular Naloxone Dose on Mu Receptor Displacement of Carfentanil in Rhesus Monkeys

by Peter J. H. Scott, Robert A. Koeppe, Xia Shao, Melissa E. Rodnick, Alexandra R. Sowa, Bradford D. Henderson, Jenelle Stauff, Phillip S. Sherman, Janna Arteaga, Dennis J. Carlo and Ronald B. Moss

Molecules 2020, 25(6), 1360; https://doi.org/10.3390/molecules25061360 - 17 Mar 2020

Cited by 8 | Viewed by 3914

Abstract

Naloxone (NLX) is a mu receptor antagonist used to treat acute opioid overdoses. Currently approved doses of naloxone to treat opioid overdoses are 4 mg intranasal (IN) and 2 mg intramuscular (IM). However, higher mu receptor occupancy (RO) may be required to treat [...] Read more.

Naloxone (NLX) is a mu receptor antagonist used to treat acute opioid overdoses. Currently approved doses of naloxone to treat opioid overdoses are 4 mg intranasal (IN) and 2 mg intramuscular (IM). However, higher mu receptor occupancy (RO) may be required to treat overdoses due to more potent synthetic opioids such as fentanyl and carfentanil that have entered the illicit drug market recently. To address this need, a higher dose of NLX has been investigated in a 5 mg IM formulation called ZIMHI but, while the effects of intravenous (IV) and IN administration of NLX on the opioid mu receptor occupancy (RO) have been studied, comparatively little is known about RO for IM administration of NLX. The goal of this study was to examine the effect of IM dosing of NLX on mu RO in rhesus macaques using [¹¹C]carfentanil positron emission tomography (PET) imaging. The lowest dose of NLX (0.06 mg/kg) approximated 51% RO. Higher doses of NLX (0.14 mg/kg, 0.28 mg/kg) resulted in higher mu RO of 70% and 75%, respectively. Plasma levels were 4.6 ng/mL, 16.8 ng/mL, and 43.4 ng/mL for the three IM doses, and a significant correlation between percent RO and plasma NLX level was observed (r = 0.80). These results suggest that higher doses of IM NLX result in higher mu RO and could be useful in combating overdoses resulting from potent synthetic opioids. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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17 pages, 2569 KiB

Open AccessArticle

Evaluation of Organo [¹⁸F]Fluorosilicon Tetrazine as a Prosthetic Group for the Synthesis of PET Radiotracers

by Sofia Otaru, Surachet Imlimthan, Mirkka Sarparanta, Kerttuli Helariutta, Kristiina Wähälä and Anu J. Airaksinen

Molecules 2020, 25(5), 1208; https://doi.org/10.3390/molecules25051208 - 7 Mar 2020

Cited by 9 | Viewed by 5111

Abstract

Fluorine-18 is the most widely used positron emission tomography (PET) radionuclide currently in clinical application, due to its optimal nuclear properties. The synthesis of ¹⁸F-labeled radiotracers often requires harsh reaction conditions, limiting the use of sensitive bio- and macromolecules as precursors for [...] Read more.

Fluorine-18 is the most widely used positron emission tomography (PET) radionuclide currently in clinical application, due to its optimal nuclear properties. The synthesis of ¹⁸F-labeled radiotracers often requires harsh reaction conditions, limiting the use of sensitive bio- and macromolecules as precursors for direct radiolabeling with fluorine-18. We aimed to develop a milder and efficient in vitro and in vivo labeling method for trans-cyclooctene (TCO) functionalized proteins, through the bioorthogonal inverse-electron demand Diels-Alder (IEDDA) reaction with fluorine-18 radiolabeled tetrazine ([¹⁸F]SiFA-Tz). Here, we used TCO-modified bovine serum albumin (BSA) as the model protein, and isotopic exchange (IE) (¹⁹F/¹⁸F) chemistry as the labeling strategy. The radiolabeling of albumin-TCO with [¹⁸F]SiFA-Tz ([¹⁸F]6), providing [¹⁸F]fluoroalbumin ([¹⁸F]10) in high radiochemical yield (99.1 ± 0.2%, n = 3) and a molar activity (MA) of 1.1 GBq/µmol, confirmed the applicability of [¹⁸F]6 as a quick in vitro fluorination reagent for the TCO functionalized proteins. While the biological evaluation of [¹⁸F]6 demonstrated defluorination in vivo, limiting the utility for pretargeted applications, the in vivo stability of the radiotracer was dramatically improved when [¹⁸F]6 was used for the radiolabeling of albumin-TCO ([¹⁸F]10) in vitro, prior to administration. Due to the detected defluorination in vivo, structural optimization of the prosthetic group for improved stability is needed before further biological studies and application of pretargeted PET imaging. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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14 pages, 2247 KiB

Open AccessArticle

Evaluation of a ⁶⁸Ga-Labeled DOTA-Tetrazine as a PET Alternative to ¹¹¹In-SPECT Pretargeted Imaging

by Patricia E. Edem, Jesper T. Jørgensen, Kamilla Nørregaard, Rafaella Rossin, Abdolreza Yazdani, John F. Valliant, Marc Robillard, Matthias M. Herth and Andreas Kjaer

Molecules 2020, 25(3), 463; https://doi.org/10.3390/molecules25030463 - 22 Jan 2020

Cited by 24 | Viewed by 4500

Abstract

The bioorthogonal reaction between a tetrazine and strained trans-cyclooctene (TCO) has garnered success in pretargeted imaging. This reaction was first validated in nuclear imaging using an ¹¹¹In-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-linked bispyridyl tetrazine (Tz) ([¹¹¹In]In-DOTA-PEG₁₁-Tz) and a TCO functionalized [...] Read more.

The bioorthogonal reaction between a tetrazine and strained trans-cyclooctene (TCO) has garnered success in pretargeted imaging. This reaction was first validated in nuclear imaging using an ¹¹¹In-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-linked bispyridyl tetrazine (Tz) ([¹¹¹In]In-DOTA-PEG₁₁-Tz) and a TCO functionalized CC49 antibody. Given the initial success of this Tz, it has been paired with TCO functionalized small molecules, diabodies, and affibodies for in vivo pretargeted studies. Furthermore, the single photon emission tomography (SPECT) radionuclide, ¹¹¹In, has been replaced with the β-emitter, ¹⁷⁷Lu and α-emitter, ²¹²Pb, both yielding the opportunity for targeted radiotherapy. Despite use of the ‘universal chelator’, DOTA, there is yet to be an analogue suitable for positron emission tomography (PET) using a widely available radionuclide. Here, a ⁶⁸Ga-labeled variant ([⁶⁸Ga]Ga-DOTA-PEG₁₁-Tz) was developed and evaluated using two different in vivo pretargeting systems (Aln-TCO and TCO-CC49). Small animal imaging and ex vivo biodistribution studies were performed and revealed target specific uptake of [⁶⁸Ga]Ga-DOTA-PEG₁₁-Tz in the bone (3.7 %ID/g, knee) in mice pretreated with Aln-TCO and tumor specific uptake (5.8 %ID/g) with TCO-CC49 in mice bearing LS174 xenografts. Given the results of this study, [⁶⁸Ga]Ga-DOTA-PEG₁₁-Tz can serve as an alternative to [¹¹¹In]In-DOTA-PEG₁₁-Tz. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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21 pages, 7228 KiB

Open AccessFeature PaperArticle

Kinetic Modelling of [⁶⁸Ga]Ga-DOTA-Siglec-9 in Porcine Osteomyelitis and Soft Tissue Infections

by Lars Jødal, Anne Roivainen, Vesa Oikonen, Sirpa Jalkanen, Søren B. Hansen, Pia Afzelius, Aage K. O. Alstrup, Ole L. Nielsen and Svend B. Jensen

Molecules 2019, 24(22), 4094; https://doi.org/10.3390/molecules24224094 - 13 Nov 2019

Cited by 12 | Viewed by 3121

Abstract

Background: [⁶⁸Ga]Ga-DOTA-Siglec-9 is a positron emission tomography (PET) radioligand for vascular adhesion protein 1 (VAP-1), a protein involved in leukocyte trafficking. The tracer facilitates the imaging of inflammation and infection. Here, we studied the pharmacokinetic modelling of [⁶⁸Ga]Ga-DOTA-Siglec-9 in [...] Read more.

Background: [⁶⁸Ga]Ga-DOTA-Siglec-9 is a positron emission tomography (PET) radioligand for vascular adhesion protein 1 (VAP-1), a protein involved in leukocyte trafficking. The tracer facilitates the imaging of inflammation and infection. Here, we studied the pharmacokinetic modelling of [⁶⁸Ga]Ga-DOTA-Siglec-9 in osteomyelitis and soft tissue infections in pigs. Methods: Eight pigs with osteomyelitis and soft tissue infections in the right hind limb were dynamically PET scanned for 60 min along with arterial blood sampling. The fraction of radioactivity in the blood accounted for by the parent tracer was evaluated with radio-high-performance liquid chromatography. One- and two-tissue compartment models were used for pharmacokinetic evaluation. Post-mortem soft tissue samples from one pig were analysed with anti-VAP-1 immunofluorescence. In each analysis, the animal’s non-infected left hind limb was used as a control. Results: Tracer uptake was elevated in soft tissue infections but remained low in osteomyelitis. The kinetics of [⁶⁸Ga]Ga-DOTA-Siglec-9 followed a reversible 2-tissue compartment model. The tracer metabolized quickly; however, taking this into account, produced more ambiguous results. Infected soft tissue samples showed endothelial cell surface expression of the Siglec-9 receptor VAP-1. Conclusion: The kinetics of [⁶⁸Ga]Ga-DOTA-Siglec-9 uptake in porcine soft tissue infections are best described by the 2-tissue compartment model. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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Review

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24 pages, 4346 KiB

Open AccessReview

Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals

by Brendan J. Evans, Andrew T. King, Andrew Katsifis, Lidia Matesic and Joanne F. Jamie

Molecules 2020, 25(10), 2314; https://doi.org/10.3390/molecules25102314 - 14 May 2020

Cited by 91 | Viewed by 11524

Abstract

The high affinity and specificity of peptides towards biological targets, in addition to their favorable pharmacological properties, has encouraged the development of many peptide-based pharmaceuticals, including peptide-based positron emission tomography (PET) radiopharmaceuticals. However, the poor in vivo stability of unmodified peptides against proteolysis [...] Read more.

The high affinity and specificity of peptides towards biological targets, in addition to their favorable pharmacological properties, has encouraged the development of many peptide-based pharmaceuticals, including peptide-based positron emission tomography (PET) radiopharmaceuticals. However, the poor in vivo stability of unmodified peptides against proteolysis is a major challenge that must be overcome, as it can result in an impractically short in vivo biological half-life and a subsequently poor bioavailability when used in imaging and therapeutic applications. Consequently, many biologically and pharmacologically interesting peptide-based drugs may never see application. A potential way to overcome this is using peptide analogues designed to mimic the pharmacophore of a native peptide while also containing unnatural modifications that act to maintain or improve the pharmacological properties. This review explores strategies that have been developed to increase the metabolic stability of peptide-based pharmaceuticals. It includes modifications of the C- and/or N-termini, introduction of d- or other unnatural amino acids, backbone modification, PEGylation and alkyl chain incorporation, cyclization and peptide bond substitution, and where those strategies have been, or could be, applied to PET peptide-based radiopharmaceuticals. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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20 pages, 4377 KiB

Open AccessReview

The Rise of Synaptic Density PET Imaging

by Guillaume Becker, Sylvestre Dammicco, Mohamed Ali Bahri and Eric Salmon

Molecules 2020, 25(10), 2303; https://doi.org/10.3390/molecules25102303 - 14 May 2020

Cited by 26 | Viewed by 4618

Abstract

Many neurological disorders are related to synaptic loss or pathologies. Before the boom of positrons emission tomography (PET) imaging of synapses, synaptic quantification could only be achieved in vitro on brain samples after autopsy or surgical resections. Until the mid-2010s, electron microscopy and [...] Read more.

Many neurological disorders are related to synaptic loss or pathologies. Before the boom of positrons emission tomography (PET) imaging of synapses, synaptic quantification could only be achieved in vitro on brain samples after autopsy or surgical resections. Until the mid-2010s, electron microscopy and immunohistochemical labelling of synaptic proteins were the gold-standard methods for such analyses. Over the last decade, several PET radiotracers for the synaptic vesicle 2A protein have been developed to achieve in vivo synapses visualization and quantification. Different strategies were used, namely radiolabelling with either ¹¹C or ¹⁸F, preclinical development in rodent and non-human primates, and binding quantification with different kinetic modelling methods. This review provides an overview of these PET tracers and underlines their perspectives and limitations by focusing on radiochemical aspects, as well as preclinical proof-of-concept and the main clinical outcomes described so far. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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17 pages, 2721 KiB

Open AccessReview

Positron Emission Tomography (PET) Radiopharmaceuticals in Multiple Myeloma

by Christos Sachpekidis, Hartmut Goldschmidt and Antonia Dimitrakopoulou-Strauss

Molecules 2020, 25(1), 134; https://doi.org/10.3390/molecules25010134 - 29 Dec 2019

Cited by 20 | Viewed by 10774

Abstract

Multiple myeloma (MM) is a plasma cell disorder, characterized by clonal proliferation of malignant plasma cells in the bone marrow. Bone disease is the most frequent feature and an end-organ defining indicator of MM. In this context, imaging plays a pivotal role in [...] Read more.

Multiple myeloma (MM) is a plasma cell disorder, characterized by clonal proliferation of malignant plasma cells in the bone marrow. Bone disease is the most frequent feature and an end-organ defining indicator of MM. In this context, imaging plays a pivotal role in the management of the malignancy. For several decades whole-body X-ray survey (WBXR) has been applied for the diagnosis and staging of bone disease in MM. However, the serious drawbacks of WBXR have led to its gradual replacement from novel imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT). PET/CT, with the tracer ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG), is now considered a powerful diagnostic tool for the detection of medullary and extramedullary disease at the time of diagnosis, a reliable predictor of survival as well as the most robust modality for treatment response evaluation in MM. On the other hand, ¹⁸F-FDG carries its own limitations as a radiopharmaceutical, including a rather poor sensitivity for the detection of diffuse bone marrow infiltration, a relatively low specificity, and the lack of widely applied, established criteria for image interpretation. This has led to the development of several alternative PET tracers, some of which with promising results regarding MM detection. The aim of this review article is to outline the major applications of PET/CT with different radiopharmaceuticals in the clinical practice of MM. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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