Porphyrins as Chelating Agents for Molecular Imaging in Nuclear Medicine

Porphyrin ligands, showing a significant affinity for cancer cells, also have the ability to chelate metallic radioisotopes to form potential diagnostic radiopharmaceuticals. They can be applied in single-photon emission computed tomography (SPECT) and positron emission tomography (PET) to evaluate metabolic changes in the human body for tumor diagnostics. The aim of this paper is to present a short overview of the main metallic radionuclides complexed by porphyrin ligands and used in these techniques. These chelation reactions are discussed in terms of the complexation conditions and kinetics and the complex stability.     

[18F]Ethenesulfonyl Fluoride as a Practical Radiofluoride Relay Reagent

Fluorine-18 is the most utilized radioisotope in positron emission tomography (PET), but the wide application of fluorine-18 radiopharmaceuticals is hindered by its challenging labelling conditions. As such, many potentially important radiotracers remain underutilized. Herein, we describe the use of [¹⁸F]ethenesulfonyl fluoride (ESF) as a novel radiofluoride relay reagent that allows radiofluorination reactions to be performed in minimally equipped satellite nuclear medicine centres. [¹⁸F]ESF has a simple and reliable production route and can be stored on inert cartridges. The cartridges can then be shipped remotely and the trapped [¹⁸F]ESF can be liberated by simple solvent elution. We have tested 18 radiolabelling precursors, inclusive of model and clinically used structures, and most precursors have demonstrated comparable radiofluorination efficiencies to those obtained using a conventionally dried [¹⁸F]fluoride source.     

[89Zr]-Pertuzumab PET Imaging Reveals Paclitaxel Treatment Efficacy Is Positively Correlated with HER2 Expression in Human Breast Cancer Xenograft Mouse Models

Paclitaxel (PTX) treatment efficacy varies in breast cancer, yet the underlying mechanism for variable response remains unclear. This study evaluates whether human epidermal growth factor receptor 2 (HER2) expression level utilizing advanced molecular positron emission tomography (PET) imaging is correlated with PTX treatment efficacy in preclinical mouse models of HER2+ breast cancer. HER2 positive (BT474, MDA-MB-361), or HER2 negative (MDA-MB-231) breast cancer cells were subcutaneously injected into athymic nude mice and PTX (15 mg/kg) was administrated. In vivo HER2 expression was quantified through [⁸⁹Zr]-pertuzumab PET/CT imaging. PTX treatment response was quantified by [¹⁸F]-fluorodeoxyglucose ([¹⁸F]-FDG) PET/CT imaging. Spearman’s correlation, Kendall’s tau, Kolmogorov–Smirnov test, and ANOVA were used for statistical analysis. [⁸⁹Zr]-pertuzumab mean standard uptake values (SUV_mean) of BT474 tumors were 4.9 ± 1.5, MDA-MB-361 tumors were 1.4 ± 0.2, and MDA-MB-231 (HER2−) tumors were 1.1 ± 0.4. [¹⁸F]-FDG SUV_mean changes were negatively correlated with [⁸⁹Zr]-pertuzumab SUV_mean (r = −0.5887, p = 0.0030). The baseline [¹⁸F]-FDG SUV_mean was negatively correlated with initial [⁸⁹Zr]-pertuzumab SUV_mean (r = −0.6852, p = 0.0002). This study shows PTX treatment efficacy is positively correlated with HER2 expression level in human breast cancer mouse models. Molecular imaging provides a non-invasive approach to quantify biological interactions, which will help in identifying chemotherapy responders and potentially enhance clinical decision-making.     

Fluorine-18 and medical imaging: Radiopharmaceuticals for positron emission tomography

Fluorine presents among its radioactive isotopes fluorine-18, that decays with a 109 min half-life and a β⁺ emission, allowing external detection of the two coincident γ photons obtained after annihilation. Production techniques (medical cyclotron), radiochemical reactions for isotope incorporation in radiopharmaceuticals and development of specific detection cameras (positron emission tomographs) allowed development of a vast investigation field in medical imaging.Applications of PET in oncology ([¹⁸F]fluorodeoxyglucose, FDG) largely improved detection and management of cancers; tracer molecules labelled with fluorine-18 also allow fruitful researches in molecular imaging.     

An efficient synthesis of ([F]fluoropropyl)quinoline-5,8-diones by rapid radiofluorination-oxidative demethylation

Since many molecules bearing quinoline-5,8-dione or fused 1,4-quinone moieties possess a wide spectrum of biological activities, efficient methods for incorporation of fluorine-18 (F-18) into quinoline-5,8-diones have received considerable attention in positron emission tomography (PET) molecular imaging studies. In this paper, we describe an efficient synthetic route for the regioselective preparation of fluoropropyl-substituted quinoline-5,8-diones on the C3, C4, and C6 positions by tert-alcohol media fluorination, followed by oxidative demethylation of the corresponding dimethoxy compound using N-bromosuccinimide (NBS) in the presence of catalytic amounts of sulfuric acid. Moreover, F-18 labeled [¹⁸F]fluoropropylquinoline-5,8-diones [¹⁸F]21-23 were prepared from the corresponding mesylate precursors by a method of rapid and efficient one-pot, two-step reactions: radiofluorination using TBA [¹⁸F]F generated under no-carrier-added (NCA) conditions; oxidative demethylation, resulting in a 45% radiochemical yield of [¹⁸F]21-23 (decay-corrected) with a total synthesis time (including HPLC purification) of 75 min and high radiochemical purity (>99%), as well as high specific activity (∼230 GBq/μmol).     

Site‐Selective,Late‐Stage C−H 18F‐Fluorination on Unprotected Peptides for Positron Emission Tomography Imaging

Peptides are often ideal ligands for diagnostic molecular imaging due to their ease of synthesis and tuneable targeting properties. However, labelling unmodified peptides with ¹⁸F for positron emission tomography (PET) imaging presents a number of challenges. Here we show the combination of photoactivated sodium decatungstate and [¹⁸F]‐N‐fluorobenzenesulfonimide effects site‐selective ¹⁸F‐fluorination at the branched position in leucine residues in unprotected and unaltered peptides. This streamlined process provides a means to directly convert native peptides into PET imaging agents under mild aqueous conditions, enabling rapid discovery and development of peptide‐based molecular imaging tools.     

Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans

Hallucinogens are a loosely defined group of compounds including LSD, N,N-dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), which can evoke intense visual and emotional experiences. We are witnessing a renaissance of research interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or single photon emission computer tomography (SPECT). In general, molecular imaging can depict the uptake and binding distribution of labelled hallucinogenic compounds or their congeners in the brain, as was shown in an early PET study with N¹-([¹¹C]-methyl)-2-bromo-LSD ([¹¹C]-MBL); displacement with the non-radioactive competitor ketanserin confirmed that the majority of [¹¹C]-MBL specific binding was to serotonin 5-HT_2A receptors. However, interactions at serotonin 5HT_1A and other classes of receptors and pleotropic effects on second messenger pathways may contribute to the particular experiential phenomenologies of LSD and other hallucinogenic compounds. Other salient aspects of hallucinogen action include permeability to the blood–brain barrier, the rates of metabolism and elimination, and the formation of active metabolites. Despite the maturation of radiochemistry and molecular imaging in recent years, there has been only a handful of PET or SPECT studies of radiolabeled hallucinogens, most recently using the 5-HT_2A/2C agonist N-(2[¹¹CH₃O]-methoxybenzyl)-2,5-dimethoxy- 4-bromophenethylamine ([¹¹C]Cimbi-36). In addition to PET studies of target engagement at neuroreceptors and transporters, there is a small number of studies on the effects of hallucinogenic compounds on cerebral perfusion ([¹⁵O]-water) or metabolism ([¹⁸F]-fluorodeoxyglucose/FDG). There remains considerable scope for basic imaging research on the sites of interaction of hallucinogens and their cerebrometabolic effects; we expect that hybrid imaging with PET in conjunction with functional magnetic resonance imaging (fMRI) should provide especially useful for the next phase of this research.     

A Practical One-Pot Synthesis of Positron Emission Tomography (PET) Tracers via Nickel-Mediated Radiofluorination

Invited for this months cover picture is the group of Professor Bernd Neumaier at the Institute of Radiochemistry and Experimental Molecular Imaging at the University Clinic of Cologne. The cover picture shows the differences in brain metabolism of a healthy young and a healthy old subject, as well as a patient suffering from Parkinsons disease (left to right) uncovered by 6-[¹⁸F]FDOPA-positron emission tomography (PET). Morbus Parkinson occurs when nerve cells that produce dopamine begin to die. The shortage of dopamine leads to movement problems in affected individuals. 6-[¹⁸F]FDOPA is extensively used to evaluate the progression of Parkinsons disease. Bold stick projections of this PET tracer, as well as a neuronal network, are seen in the background. Unfortunately, conventional procedures to produce 6-[¹⁸F]FDOPA are cumbersome. Thus, several recent developments aim at the simplification of this radiosynthesis. In our work, we studied the applicability of the recently reported Ni-mediated radiofluorination approach for daily routine production of 6-[¹⁸F]FDOPA. For more details, see the Full Paper on p. 457 ff.     

A Review on the Current State and Future Perspectives of [99mTc]Tc-Housed PSMA-i in Prostate Cancer

Recently, prostate-specific membrane antigen (PSMA) has gained momentum in tumor nuclear molecular imaging as an excellent target for both the diagnosis and therapy of prostate cancer. Since 2008, after years of preclinical research efforts, a plentitude of radiolabeled compounds mainly based on low molecular weight PSMA inhibitors (PSMA-i) have been described for imaging and theranostic applications, and some of them have been transferred to the clinic. Most of these compounds include radiometals (e.g., ⁶⁸Ga, ⁶⁴Cu, ¹⁷⁷Lu) for positron emission tomography (PET) imaging or endoradiotherapy. Nowadays, although the development of new PET tracers has caused a significant drop in single-photon emission tomography (SPECT) research programs and the development of new technetium-99m (^99mTc) tracers is rare, this radionuclide remains the best atom for SPECT imaging owing to its ideal physical decay properties, convenient availability, and rich and versatile coordination chemistry. Indeed, ^99mTc still plays a relevant role in diagnostic nuclear medicine, as the number of clinical examinations based on ^99mTc outscores that of PET agents and ^99mTc-PSMA SPECT/CT may be a cost-effective alternative for ⁶⁸Ga-PSMA PET/CT. This review aims to give an overview of the specific features of the developed [^99mTc]Tc-tagged PSMA agents with particular attention to [^99mTc]Tc-PSMA-i. The chemical and pharmacological properties of the latter will be compared and discussed, highlighting the pros and cons with respect to [⁶⁸Ga]Ga-PSMA11.     

Azeotropic drying-free aliphatic radiofluorination to produce PET radiotracers in a mixed organic solvent system

Efficient aliphatic radiofluorination in a mixed organic solvent system was investigated. This method obviates the time-consuming [¹⁸F]fluoride drying step routinely required in the preparation of most fluorine-18 positron emission tomography (PET) radiotracers. The [¹⁸F]fluoride ions eluted from a QMA (quaternary ammonium anion exchange) cartridge with phase transfer agents were directly mixed in various organic solvents for subsequent radiofluorination. Herein, we report the azeotropic drying-free radiofluorination of aliphatic substrates and demonstrate the viability of hydrated [¹⁸F]fluoride ions in a mixed organic solvent system for obtaining useful radiochemical yields (RCYs). This practical and simple method has demonstrated general applicability to the production of established PET tracers as well as to the rapid assessment and chemical optimization of early-stage potential radiotracers.     

18F-FDG PET/CT显像联合肿瘤标志物检查对女性不明原因腹腔积液的诊断价值

本文探讨了18 F-脱氧葡萄糖(18 F-FDG)正电子发射计算机断层显像(PET/CT)联合肿瘤标志物检查对女性不明原因腹腔积液的鉴别诊断价值。选取95例不明原因腹腔积液女性患者的18 F-FDG PET/CT影像资料及肿瘤标志物资料进行回顾性分析,并与病理诊断结果进行对照。结果显示:95例患者中,经病理证实恶性腹腔积液74例,良性腹腔积液21例。PET/CT对良恶性腹腔积液的诊断灵敏度为98.65%,特异度为19.05%,准确度为81.05%。恶性腹腔积液的SUV max与良性腹腔积液比较,差异无统计学意义(P>0.05)。将患者按病因进一步细分后发现,卵巢癌组的SUV max明显高于其他良性原因组(P<0.05),但与结核组和其他恶性肿瘤组比较,差异无统计学意义(P>0.05)。肿瘤标志物中以CA125检测效率最高,其对卵巢癌及结核所致腹腔积液的诊断灵敏度为98.2%,特异度为7.7%,准确度为81.4%。PET/CT和CA125联合诊断对卵巢癌及结核所致腹腔积液的灵敏度、特异度及准确度与单一PET/CT或CA125诊断比较差异均无统计学意义(P>0.05)。本实验表明18 F-FDG PET/CT诊断女性不明原因腹腔积液的良恶性有较高的灵敏度和准确度,但特异性较差,联合肿瘤标志物检查并不能提高对卵巢癌及结核所致腹腔积液的诊断效能。     

Quality control of PET radiopharmaceuticals by high‐performance liquid chromatography with tris(2,2′‐bipyridyl)ruthenium(II) electrogenerated chemiluminescence detection

A highly sensitive reversed‐phase liquid chromatographic (HPLC) method was investigated to analyze a range of positron emission tomography (PET) radiopharmaceuticals using electrogenerated chemiluminescence (ECL) detection. ECL is based on the reaction of PET molecules with tris(2,2′‐bipyridyl)ruthenium(III) [Ru(bpy)₃³⁺], which is generated through the on‐line electro‐oxidation of Ru(bpy)₃²⁺. In 21 different radiopharmaceuticals studied, 18 compounds could be detected with detection limits (signal‐to‐noise ratio = 3) of 0.12–72 ng/mL per 20 μL injection. Sufficient reproducibility and linearity were obtained for the quantitative determination of PET molecules in pharmaceutical fluid. This method could be successfully applied to quality control tests of PET radiopharmaceuticals with ultra‐high specific radioactivity. Copyright © 2009 John Wiley & Sons, Ltd.     

[124I]IBETA: A New Aβ Plaque Positron Emission Tomography Imaging Agent for Alzheimer’s Disease

Several fluorine-18-labeled PET β-amyloid (Aβ) plaque radiotracers for Alzheimer’s disease (AD) are in clinical use. However, no radioiodinated imaging agent for Aβ plaques has been successfully moved forward for either single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Radioiodinated pyridyl benzofuran derivatives for the SPECT imaging of Aβ plaques using iodine-123 and iodine-125 are being pursued. In this study, we assess the iodine-124 radioiodinated pyridyl benzofuran derivative 5-(5-[¹²⁴I]iodobenzofuran-2-yl)-N,N-dimethylpyridin-2-amine ([¹²⁴I]IBETA) (Ki = 2.36 nM) for utilization in PET imaging for Aβ plaques. We report our findings on the radioiododestannylation reaction used to prepare [^124/125I]IBETA and evaluate its binding to Aβ plaques in a 5 × FAD mouse model and postmortem human AD brain. Both [¹²⁵I]IBETA and [¹²⁴I]IBETA are produced in >25% radiochemical yield and >85% radiochemical purity. The in vitro binding of [¹²⁵I]IBETA and [¹²⁴I]IBETA in transgenic 5 × FAD mouse model for Aβ plaques was high in the frontal cortex, anterior cingulate, thalamus, and hippocampus, which are regions of high Aβ accumulation, with very little binding in the cerebellum (ratio of brain regions to cerebellum was >5). The in vitro binding of [¹²⁵I]IBETA and [¹²⁴I]IBETA in postmortem human AD brains was higher in gray matter containing Aβ plaques compared to white matter (ratio of gray to white matter was >5). Anti-Aβ immunostaining strongly correlated with [¹²⁴/¹²⁵I]IBETA regional binding in both the 5 × FAD mouse and postmortem AD human brains. The binding of [¹²⁴/¹²⁵I]IBETA in 5 × FAD mouse and postmortem human AD brains was displaced by the known Aβ plaque imaging agent, Flotaza. Preliminary PET/CT studies of [¹²⁴I]IBETA in the 5 × FAD mouse model suggested [¹²⁴I]IBETA was relatively stable in vivo with a greater localization of [¹²⁴I]IBETA in the brain regions with a high concentration of Aβ plaques. Some deiodination was observed at later time points. Therefore, [¹²⁴I]IBETA may potentially be a useful PET radioligand for Aβ plaques in brain studies.     

Novel Radioiodinated and Radiofluorinated Analogues of FT-2102 for SPECT or PET Imaging of mIDH1 Mutant Tumours

Isocitrate dehydrogenases (IDHs) are metabolic enzymes commonly mutated in human cancers (glioma, acute myeloid leukaemia, chondrosarcoma, and intrahepatic cholangiocarcinoma). These mutated variants of IDH (mIDH) acquire a neomorphic activity, namely, conversion of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate involved in tumourigenesis. Thus, mIDHs have emerged as highly promising therapeutic targets, and several mIDH specific inhibitors have been developed. However, the evaluation of mIDH status, currently performed by biopsy, is essential for patient stratification and thus treatment and follow-up. We report herein the development of new radioiodinated and radiofluorinated analogues of olutasidenib (FT-2102) as tools for noninvasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging of mIDH1 up- and dysregulation in tumours. Nonradiolabelled derivatives 2 and 3 halogenated at position 6 of the quinolinone scaffold were synthesised and tested in vitro for their inhibitory potencies and selectivities in comparison with the lead compound FT-2102. Using a common organotin precursor, (S)-[¹²⁵I]2 and (S)-[¹⁸F]3 were efficiently synthesised by radio-iododemetallation and copper-mediated radiofluorination, respectively. Both radiotracers were stable at room temperature in saline or DPBS solution and at 37 °C in mouse serum, allowing future planning of their in vitro and in vivo evaluations in glioma and chondrosarcoma models.     

19F MRI Probes for Multimodal Imaging**

Magnetic resonance imaging (MRI) is one of the most powerful imaging tools today, capable of displaying superior soft-tissue contrast. This review discusses developments in the field of ¹⁹F MRI multimodal probes in combination with optical fluorescence imaging (OFI), ¹H MRI, chemical exchange saturation transfer (CEST) MRI, ultrasonography (USG), X-ray computed tomography (CT), single photon emission tomography (SPECT), positron emission tomography (PET), and photoacoustic imaging (PAI). In each case, multimodal ¹⁹F MRI probes compensate for the deficiency of individual techniques and offer improved sensitivity or accuracy of detection over unimodal counterparts. Strategies for designing ¹⁹F MRI multimodal probes are described with respect to their structure, physicochemical properties, biocompatibility, and the quality of images.     

Cover Picture: A Practical One-Pot Synthesis of Positron Emission Tomography (PET) Tracers via Nickel-Mediated Radiofluorination (ChemistryOpen 4/2015)

Invited for this months cover picture is the group of Professor Bernd Neumaier at the Institute of Radiochemistry and Experimental Molecular Imaging at the University Clinic of Cologne. The cover picture shows the differences in brain metabolism of a healthy young and a healthy old subject, as well as a patient suffering from Parkinsons disease (left to right) uncovered by 6-[¹⁸F]FDOPA-positron emission tomography (PET). Morbus Parkinson occurs when nerve cells that produce dopamine begin to die. The shortage of dopamine leads to movement problems in affected individuals. 6-[¹⁸F]FDOPA is extensively used to evaluate the progression of Parkinsons disease. Bold stick projections of this PET tracer, as well as a neuronal network, are seen in the background. Unfortunately, conventional procedures to produce 6-[¹⁸F]FDOPA are cumbersome. Thus, several recent developments aim at the simplification of this radiosynthesis. In our work, we studied the applicability of the recently reported Ni-mediated radiofluorination approach for daily routine production of 6-[¹⁸F]FDOPA. For more details, see the Full Paper on p. 457 ff.     

Methods and applications of positron-based medical imaging

Positron emission tomography (PET) is a diagnostic imaging method to examine metabolic functions and their disorders. Dedicated ring systems of scintillation detectors measure the 511 keV γ-radiation produced in the course of the positron emission from radiolabelled metabolically active molecules. A great number of radiopharmaceuticals labelled with ¹¹C, ¹³N, ¹⁵O, or ¹⁸F positron emitters have been applied both for research and clinical purposes in neurology, cardiology and oncology. The recent success of PET with rapidly increasing installations is mainly based on the use of [¹⁸F]fluorodeoxyglucose (FDG) in oncology where it is most useful to localize primary tumours and their metastases.     

An Improved Synthesis of N-(4-[18F]Fluorobenzoyl)-Interleukin-2 for the Preclinical PET Imaging of Tumour-Infiltrating T-cells in CT26 and MC38 Colon Cancer Models

Positron emission tomography (PET) imaging of activated T-cells with N-(4-[¹⁸F]fluorobenzoyl)-interleukin-2 ([¹⁸F]FB-IL-2) may be a promising tool for patient management to aid in the assessment of clinical responses to immune therapeutics. Unfortunately, existing radiosynthetic methods are very low yielding due to complex and time-consuming chemical processes. Herein, we report an improved method for the synthesis of [¹⁸F]FB-IL-2, which reduces synthesis time and improves radiochemical yield. With this optimized approach, [¹⁸F]FB-IL-2 was prepared with a non-decay-corrected radiochemical yield of 3.8 ± 0.7% from [¹⁸F]fluoride, 3.8 times higher than previously reported methods. In vitro experiments showed that the radiotracer was stable with good radiochemical purity (>95%), confirmed its identity and showed preferential binding to activated mouse peripheral blood mononuclear cells. Dynamic PET imaging and ex vivo biodistribution studies in naïve Balb/c mice showed organ distribution and kinetics comparable to earlier published data on [¹⁸F]FB-IL-2. Significant improvements in the radiochemical manufacture of [¹⁸F]FB-IL-2 facilitates access to this promising PET imaging radiopharmaceutical, which may, in turn, provide useful insights into different tumour phenotypes and a greater understanding of the cellular nature and differential immune microenvironments that are critical to understand and develop new treatments for cancers.     

Synthesis of 18F‐Difluoromethylarenes from Aryl (Pseudo) Halides

A general method for the synthesis of [¹⁸F]difluoromethylarenes from [¹⁸F]fluoride for radiopharmaceutical discovery is reported. The method is practical, operationally simple, tolerates a wide scope of functional groups, and enables the labeling of a variety of arenes and heteroarenes with radiochemical yields (RCYs, not decay‐corrected) from 10 to 60 %. The ¹⁸F‐fluorination precursors are readily prepared from aryl chlorides, bromides, iodides, and triflates. Seven ¹⁸F‐difluoromethylarene drug analogues and radiopharmaceuticals including Claritin, fluoxetine (Prozac), and [¹⁸F]DAA1106 were synthesized to show the potential of the method for applications in PET radiopharmaceutical design.     

Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography

Positron emission tomography (PET) is a powerful and rapidly developing area of molecular imaging that is used to study and visualize human physiology by the detection of positron-emitting radiopharmaceuticals. Information about metabolism, receptor/enzyme function, and biochemical mechanisms in living tissue can be obtained directly from PET experiments. Unlike magnetic resonance imaging (MRI) or computerized tomography (CT), which mainly provide detailed anatomical images, PET can measure chemical changes that occur before macroscopic anatomical signs of a disease are observed. PET is emerging as a revolutionary method for measuring body function and tailoring disease treatment in living subjects. The development of synthetic strategies for the synthesis of new positron-emitting molecules is, however, not trivial. This Review highlights key aspects of the synthesis of PET radiotracers with the short-lived positron-emitting radionuclides (11)C, (18)F, (15)O, and (13)N, with emphasis on the most recent strategies.