Positron Emission Tomography Molecular Imaging Research Articles

Folate receptor-targeted multimodality imaging of ovarian cancer in a novel syngeneic mouse model.

A new transplantable ovarian tumor model is presented using a novel folate receptor (FR) positive, murine ovarian cancer cell line that emulates the human disease and induces widespread intraperitoneal (i.p.) tumors in immunocompetent mice within 4–8 weeks of implantation. Tumor development was monitored using a new positron emission tomography (PET) FR-targeting reporter with PET/computerized tomography (PET/CT) and fluorescence molecular tomography (FMT) using a commercial FR-targeting reporter. Conventional structural magnetic resonance imaging (MRI) was also performed. Adult female C57BL/6 mice were injected i.p. with 6 × 106 MKP-L FR+ cells. Imaging was performed weekly beginning 2 weeks after tumor induction. The albumin-binding, FR-targeting ligand cm09 was radiolabeled with the positron emitter 68Ga and used to image the tumors with a small animal PET/CT. The FR-reporter FolateRSense 680 (PerkinElmer) was used for FMT and flow cytometry. Preclinical MRI (7 T) without FR-targeting was compared with the PET and FMT molecular imaging. Tumors were visible by all three imaging modalities. PET/CT had the highest imaging sensitivity at 3–3.5 h postadministration (mean %IA/g mean > 6) and visualized tumors earlier than the other two modalities with lower kidney uptake (mean %IA/g mean < 17) than previously reported FR-targeting agents in late stage disease. FMT showed relatively low FR-targeted agent in the bladder and kidneys, but yielded the lowest anatomical image resolution. MRI produced the highest resolution images, but it was difficult to distinguish tumors from abdominal organs during early progression since a FR-targeting MRI reporter was not used. Nevertheless, there was good correlation of imaging biomarkers between the three modalities. Tumors in the mouse ovarian cancer model could be detected using FR-targeted imaging as early as 2 weeks post i.p. injection of tumor cells. An imaging protocol should combine one or more of the modalities, e.g., PET/CT or PET/MRI for optimal tumor detection and delineation from surrounding tissues.

PET tracers for imaging brain α7 nicotinic receptors: an update.

Positron emission tomography (PET) molecular imaging of brain targets is a powerful tool to diagnose, follow up, and develop treatments and personalized medicine for a number of acute and chronic brain disorders. The availability of β+ emitter tracers labelled with [(11)C] or [(18)F] having optimal characteristics of affinity and selectivity for alpha-7 nicotinic receptors (α7R) has received considerable attention, due to the major implication of these receptors in brain functions. The aim of this review is to identify the interest and need for the in vivo exploration of α7R by PET molecular imaging, which tools are currently available for this and how to progress.

PET molecular imaging of angiogenesis with a multiple tyrosine kinase receptor-targeted agent in a rat model of myocardial infarction.

Angiogenesis plays a major role in tissue remodeling and repair after myocardial infarction (MI), and imaging it could provide information on the healing process. During angiogenesis, vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), and Tie receptors are upregulated, and this study aimed to develop a C-11 positron emission tomography (PET) agent for imaging angiogenesis by targeting these receptors. A VEGFR-2/Tie-2/PDGFRα inhibitor (N-(6-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)-ureido]-phenoxy}-1H-benzoimidazol-2-yl)-2-(4-methyl-piperazin-1-yl)-acetamide (ATV-1)) was synthesized and labeled with C-11. MicroPET imaging of a rat MI model was compared to proteins expression by immunohistochemistry. [(11)C]ATV-1 specifically accumulated in the infracted region of the left ventricular (LV) lateral wall more than in the interventricular septal wall, but not in sham-operated or healthy animals. Moreover, [(11)C]ATV-1 uptake in the LV significantly correlated with Tie-2, VEGFR-2, and PDGFRα expression. Imaging angiogenesis in MI rats using [(11)C]ATV-1 and PET has been demonstrated. These results merit further research and development of more hydrophilic modified [(11)C]ATV-1 as a PET tracer.

INDs for PET molecular imaging probes-approach by an academic institution.

We have developed an efficient, streamlined, cost-effective approach to obtain Investigational New Drug (IND) approvals from the Food and Drug Administration (FDA) for positron emission tomography (PET) imaging probes (while the FDA uses the terminology PET drugs, we are using “PET imaging probes,” “PET probes,” or “probes” as the descriptive terms). The required application and supporting data for the INDs were collected in a collaborative effort involving appropriate scientific disciplines. This path to INDs was successfully used to translate three [18 F]fluoro-arabinofuranosylcytosine (FAC) analog PET probes to phase 1 clinical trials. In doing this, a mechanism has been established to fulfill the FDA regulatory requirements for translating promising PET imaging probes from preclinical research into human clinical trials in an efficient and cost-effective manner.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-014-0735-2) contains supplementary material, which is available to authorized users.

Recent Findings and Newer Paradigms of Neuroimaging Research in Geriatric Psychiatry

Over the past several decades, there has been a significant increase in the population of older adults and associated mental health problems throughout the world. For older adults, mental health problems such as dementia, depression, psychosis, and anxiety disorders can be debilitating and reduce the overall health and quality of life. Moreover, as most of the geriatric psychiatric disorders are not easily diagnosed and treated, it is important to understand the neurobiological mechanisms of these disorders, as this understanding promises to improve clinical care. In this regard, a large number of neuroimaging techniques are being developed and are used for research, with some ultimately entering clinical practice. In 1999, the special issue of the Journal of Geriatric Psychiatry and Neurology reviewed a broad spectrum of neuroimaging and related modalities such as magnetic resonance imaging (MRI), magnetic resonance spectroscopy, positron emission tomography (PET), quantitative electroencephalogram, and computed tomography with comprehensive articles describing methods and observations in normal aging and related psychopathologic states. Since 1999, there has been even further significant progress in neuroimaging research. Molecular imaging using PET can detect detrimental effects occurring in the brain on a molecular basis. The recent advances in structural and functional MRI methodologies open the ways to application of neuroimaging techniques to common clinical situations such as diagnosis and personalized treatment. Moreover, advances in network theory may enable us to understand the pathophysiological mechanisms in the brain as a disruption to a network. This special issue of the Journal of Geriatric Psychiatry and Neurology brings together internationally recognized experts in the imaging field to address these key issues. Reza Tadayonnejad and Olusola Ajilore discuss brain network dysfunction in late-life depression. To date, several studies have highlighted structural and functional abnormalities of frontal, striatal, temporal, and parietal areas in late-life depression. These abnormalities might result in a broad range of negative impacts on mood, cognition, and global functioning in patients with late-life depression. Although the widespread nature of structural damage in latelife depression is suggestive of a system disorder resulting in disrupted networks, studies based on the univariate statistical approaches for analyzing functional and structural imaging have a limited ability to test such hypotheses. In this regard, multivariate and patternwise perspectives using network theory provide a new paradigm for understanding the complex neurobiological mechanisms of late-life depression. In this review, a network dysfunction model is used as a conceptual framework for reviewing recent neuroimaging findings in late-life depression. Kentaro Hirao and Gwen Smith discuss recent developments in the molecular imaging using PET in late-life depression. With the development of sensitive and accurate instrumentation and radiotracer chemistry, molecular PET imaging can detect in vivo the precise neurobiological process of various geriatric neuropsychiatric disorders including Alzheimer disease, Parkinson disease, and late-life depression. They review the recent advances and literature in molecular imaging in geriatric psychiatric disease, with a focus on late-life depression. Interestingly, they provide the future directions of the molecular imaging studies integrating molecular imaging with genetic, neuropsychiatric, and cognitive outcomes, multimodality neuroimaging. Howard Aizenstein and colleagues discuss the clinical application of the neuroimaging methods to predict the treatment response to antidepressant medications. A number of imaging studies have demonstrated that pretreatment structural and functional MRI markers are predictive of an individual’s response to standard antidepressant pharmacotherapy. This article reviews the literature on MRI prediction of treatment response and discusses how these findings can be relevant to personalizing treatment of late-life depression. Chris Abott discusses the several reports of neuroimaging studies on longitudinal electroconvulsive therapy (ECT). The ECT is known to be one of the most effective treatments for refractory depression and other psychiatric disorders; however, the precise neurobiological mechanism of action and neural correlates of treatment response are poorly understood.

18F-labeling techniques for positron emission tomography

Much research effort has been made to understand various biological processes at levels of molecules using molecular imaging techniques. Because of great sensitivity, high resolution, and rapid detection, positron emission tomography (PET) imaging is becoming one of the most used imaging techniques for medical diagnose and pre-clinical studies. Here we provide a review on molecular imaging and PET imaging. An introduction is also provided on 18F-fluorine labeling techniques for the preparation of PET imaging probes. A summary and comparison of currently available 18F-fluorine labeling methods is provided. The perspectives for 18F-fluorine labeling techniques are also given.

Determining efficacy of breast cancer therapy by PET imaging of HER2 mRNA

Monitoring the effectiveness of therapy early and accurately continues to be challenging. We hypothesize that determination of Human Epidermal Growth Factor Receptor 2 (HER2) mRNA in malignant breast cancer (BC) cells by positron emission tomography (PET) imaging, before and after treatment, would reflect therapeutic efficacy. WT4340, a peptide nucleic acid (PNA) 12-mer complementary to HER2 mRNA was synthesized together with -CSKC, a cyclic peptide, which facilitated internalization of the PNA via IGFR expressed on BC cells, and DOTA that chelated Cu-64. Mice (n = 8) with BT474 ER+/HER2+ human BC received doxorubicin (DOX, 1.5mg/kg) i.p. once a week for six weeks. Mice (n = 8) without DOX served as controls. All mice were PET imaged with F-18-FDG and 48 h later with Cu-64-WT4340. PET imaging were performed before and 72 h after each treatment. Standardized uptake values (SUVs) were determined and percent change calculated. Animal body weight (BW) and tumor volume (TV) were measured. SUVs for Cu-64-WT4340 after DOX treatment declined by 54% ± 17% after the second dose, 41% ± 15% after the fourth dose, and 29% ± 7% after the sixth dose, compared with 42% ± 22%, 31% ± 18%, and 13% ± 9% (p<0.05) for F-18-FDG. In untreated mice, the corresponding percent SUVs for Cu-64-WT4340 were 145% ± 82%, 165% ± 39%, and 212% ± 105% of pretreatment SUV, compared with 108% ± 28%, 151% ± 8%, and 152% ± 35.5%, (p<0.08) for F-18-FDG. TV in mice after second dose was 114.15% ± 61.83%, compared with 144.7% ± 64.4% for control mice. BW of DOX-treated mice was 103.4% ± 7.6% of pretreatment, vs. 100.1% ± 4.3% for control mice. Therapeutic efficacy was apparent sooner by molecular PET imaging than by determination of reduction in TV.

Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics

Positron emission tomography (PET) is a noninvasive molecular imaging technology that is becoming increasingly important for the measurement of physiologic, biochemical, and pharmacological functions at cellular and molecular levels in patients with cancer. Formation, development, and aggressiveness of tumor involve a number of molecular pathways, including intrinsic tumor cell mutations and extrinsic interaction between tumor cells and the microenvironment. Currently, evaluation of these processes is mainly through biopsy, which is invasive and limited to the site of biopsy. Ongoing research on specific target molecules of the tumor and its microenvironment for PET imaging is showing great potential. To date, the use of PET for diagnosing local recurrence and metastatic sites of various cancers and evaluation of treatment response is mainly based on [(18)F]fluorodeoxyglucose ([(18)F]FDG), which measures glucose metabolism. However, [(18)F]FDG is not a target-specific PET tracer and does not give enough insight into tumor biology and/or its vulnerability to potential treatments. Hence, there is an increasing need for the development of selective biologic radiotracers that will yield specific biochemical information and allow for noninvasive molecular imaging. The possibility of cancer-associated targets for imaging will provide the opportunity to use PET for diagnosis and therapy response monitoring (theranostics) and thus personalized medicine. This article will focus on the review of non-[(18)F]FDG PET tracers for specific tumor biology processes and their preclinical and clinical applications.

Carbon‐11 and fluorine‐18 chemistry devoted to molecular probes for imaging the brain with positron emission tomography

Exploration of the living human brain in real-time and in a noninvasive way was for centuries only a dream, made, however, possible today with the remarkable development during the four last decades of powerful molecular imaging techniques, and especially positron emission tomography (PET). Molecular PET imaging relies, from a chemical point of view, on the use and preparation of a positron-emitting radiolabelled probe or radiotracer, notably compounds incorporating one of two short-lived radionuclides fluorine-18 (T1/2 : 109.8 min) and carbon-11 (T1/2 : 20.38 min). The growing availability and interest for the radiohalogen fluorine-18 in radiopharmaceutical chemistry undoubtedly results from its convenient half-life and the successful use in clinical oncology of 2-[(18) F]fluoro-2-deoxy-d-glucose ([(18) F]FDG). The special interest of carbon-11 is not only that carbon is present in virtually all biomolecules and drugs allowing therefore for isotopic labelling of their chemical structures but also that a given molecule could be radiolabelled at different functions or sites, permitting to explore (or to take advantage of) in vivo metabolic pathways. PET chemistry includes production of these short-lived radioactive isotopes via nuclear transmutation reactions using a cyclotron, and is directed towards the development of rapid synthetic methods, at the trace level, for the introduction of these nuclides into a molecule, as well as the use of fast purification, analysis and formulation techniques. PET chemistry is the driving force in molecular PET imaging, and this special issue of the Journal of Labelled Compounds and Radiopharmaceuticals, which is strongly chemistry and radiochemistry-oriented, aims at illustrating, be it in part only, the state-of-the-art arsenal of reactions currently available and its potential for the research and development of specific molecular probes labelled with the positron emitters carbon-11 and fluorine-18, with optimal imaging properties for PET exploration of the brain.

Gallium-68: Chemistry and Radiolabeled Peptides Exploring Different Oncogenic Pathways

Abstract Early and specific tumor detection and also therapy selection and response evaluation are some challenges of personalized medicine. This calls for high sensitive and specific molecular imaging such as positron emission tomography (PET). The use of peptides for PET molecular imaging has undeniable advantages: possibility of targeting through peptide-receptor interaction, small size and low-molecular weight conferring good penetration in the tissue or at cellular level, low toxicity, no antigenicity, and possibility of wide choice for radiolabeling. Among β(+)-emitter radioelements, Gallium-68 is a very attractive positron-emitter compared with carbon-11 or fluorine-18 taking into account its easy production via a (68)Ge/(68)Ga generator and well established radiochemistry. Gallium-68 chemistry is based on well-defined coordination complexes with macrocycle or chelates having strong binding properties, particularly suitable for linking peptides that allow resistance to in vivo transchelation of the metal ion. Understanding specific and nonspecific molecular mechanisms involved in oncogenesis is one major key to develop new molecular imaging tools. The present review focuses on peptide signaling involved in different oncogenic pathways. This peptide signalization might be common for tumoral and non-tumoral processes or could be specific of an oncological process. This review describes gallium chemistry and different (68)Ga-radiolabeled peptides already in use or under development aiming at developing molecular PET imaging of different oncological processes.

Molecular Imaging-based Early-Phase and Exploratory Clinical Research

In vivo molecular imaging became a key technology for innovative drug development. Especially, positron emission tomography (PET) has been applied to patho-physiological science, pharmacodynamics/pharmacokinetics (PD/PK) studies, and drug delivery system (DDS) studies, and accelerated the paradigm shift not only from experimental animals to human subjects, but also from PK in blood circulation to PK in target tissues, even in human. Our RIKEN Centre for Molecular Imaging Science has been established to promote such innovative drug developmental studies with PET molecular imaging, as a center of excellence for development of molecular probes. The center is creating novel labeling methods on drug candidate molecules with positron-emitting radionuclides, and is providing the molecular probes suitable for targeting bio-functional molecules and cellular functions, which are useful for evaluation of drug efficacy and pharmacokinetics in human subjects. Animal PET studies with mice, rats, rabbits, marmosets, and macaque monkeys have also been promoted both under anesthetic condition and consciousness, which was a really difficult task but important for comparison with human PET studies. In this sense, mutual collaboration between the research consortia in basic PET field and in clinical PET molecular imaging such as Osaka City University Hospital would be of great value. Here, the concept, outline of our activities, and PK/PD studies with efficient application of molecular imaging is presented. In addition, the results of the first cassette-dose and micro-dose clinical trials approved by Pharmaceuticals and Medical Devices Agency (PMDA) (New Energy and Industrial Technology Development Organization (NEDO) project represented by Prof. Yuichi Sugiyama) are described.

Bringing New PET drugs to clinical practice - a regulatory perspective.

The regulatory framework for radioactive drugs, in particular those used in positron emission tomography (PET) scans, has been gradually established since the release of the Food and Drug Administration Modernization Act in 1997. Various guidances specially tailored to accommodate special properties of PET drugs have been issued by the Food and Drug Administration (FDA) in order to ensure this valuable technology (i.e., PET molecular imaging) will continue to be available to patients and yet the safety and efficacy of PET drugs are well regulated so that public health will be protected. This article presents several key elements of this regulatory framework for PET drugs. New regulatory avenues proposed by the FDA to facilitate the research and development process to bring more new PET drugs to clinical practice, as well as to foster the opportunity of using “orphan” PET drugs in clinical practice are also discussed in this paper.

A model System for Validation of PET Radiopharmaceuticals: Focusing on Tumor Microenvironment

Positron emission tomography (PET) imaging has emerged as an important clinical tool for cancer management, and specifically targeted radiopharmaceuticals play critical roles on PET molecular imaging. Solid cancers have highly complex and heterogeneous microenvironment, this review focused on those microenvironmental factors such as hypoxia, proliferation and perfusion and, accordingly, a novel test system for validation of current and novel targeted imaging radiopharmaceuticals. In this review, we have introduced the establishment of cancer and metastases models in nude mice, visualization of microenvironmental components of hypoxia, proliferation, perfusion, stroma and necrosis in cancers and metastases for establishing the microenvironment based model system, and validation of several radio- pharmaceuticals such as 18F-fluoro-2-deoxyglucose (18F-FDG) 18F-fluorothymidine (18F-FLT), 18F-misonidazole (18F- FMISO) using the system. We found that 18F-FLT accumulates in proliferating cancer cells, while 18F-FMISO and 18F-FDG mostly accumulate in hypoxic and non-proliferative cancer cells, 18F-FDG shares roughly similar intratumoral distribution pattern with 18F-FMISO and IAZGP, but mutually excludes 18F-FLT. This model system validated current tracers for imaging glucose metabolism, hypoxia and proliferation in cancer and metastases, therefore, can be used for novel targeted radiopharmaceuticals validation.

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT7 Receptor Imaging with PET

The most recently discovered serotonin (5-HT) receptor subtype, 5-HT(7), is considered to be associated with several CNS disorders. Noninvasive in vivo positron emission tomography (PET) studies of cerebral 5-HT(7) receptors could provide a significant advance in the understanding of the neurobiology and eventual dysfunctions of the 5-HT(7) receptor. To date, no appropriate 5-HT(7) receptor PET ligand has been developed. Here, we modified known 5-HT(7) selective phenylpiperazinyl-butyloxindole derivatives so that they may be labeled either with carbon-11 or fluorine-18. A set of potential 5-HT(7) ligands for PET molecular imaging was successfully synthesized. Two compounds (10 and 14) were tested against a range of targets. Both compounds display a promising in vitro profile with respect to PET imaging of the 5-HT(7) receptor in thalamic regions.

Toward truly combined PET/CT imaging using PET detectors and photon counting CT with iterative reconstruction implementing physical detector response

This paper intends to demonstrate the feasibility of truly combined PET/CT imaging and addresses some of the major challenges raised by this dual modality approach. A method is proposed to retrieve maximum accuracy out of limited resolution computed tomography (CT) scans acquired with positron emission tomography (PET) detectors. A PET/CT simulator was built using the LabPET™ detectors and front-end electronics. Acquisitions of energy-binned data sets were made using this low spatial resolution CT system in photon counting mode. To overcome the limitations of the filtered back-projection technique, an iterative reconstruction library was developed and tested for the counting mode CT. Construction of the system matrix is based on a preregistered raster scan from which the experimental detector response is obtained. PET data were obtained sequentially with CT in a conventional manner. A meticulous description of the system geometry and misalignment corrections is imperative and was incorporated into the matrix definition to achieve good image quality. Using this method, no sinogram precorrection or interpolation is necessary and measured projections can be used as raw input data for the iterative reconstruction algorithm. Genuine dual modality PET/CT images of phantoms and animals were obtained for the first time using the same detection platform. CT and fused PET/CT images show that LabPET™ detectors can be successfully used as individual X-ray photon counting devices for low-dose CT imaging of the anatomy in a molecular PET imaging context.

F-18 Labeling Protocol of Peptides Based on Chemically Orthogonal Strain-Promoted Cycloaddition under Physiologically Friendly Reaction Conditions

We introduce the high-throughput synthesis of various (18)F-labeled peptide tracers by a straightforward (18)F-labeling protocol based on a chemo-orthogonal strain-promoted alkyne azide cycloaddition (SPAAC) using aza-dibenzocyclootyne-substituted peptides as precursors with (18)F-azide synthon to develop peptide based positron emission tomography (PET) molecular imaging probes. The SPAAC reaction and subsequent chemo-orthogonal purification reaction with azide resin proceeded quickly and selectively under physiologically friendly reaction conditions (i.e., toxic chemical reagents-free, aqueous medium, room temperature, and pH ≈7), and provided four (18)F-labeled tumor targetable bioactive peptides such as cyclic Arg-Gly-Asp (cRGD) peptide, bombesin (BBN), c-Met binding peptide (cMBP), and apoptosis targeting peptide (ApoPep) in high radiochemical yields as direct injectable solutions without any HPLC purification and/or formulation processes. In vitro binding assay and in vivo PET molecular imaging study using the (18)F-labeled cRGD peptide also demonstrated a successful application of our (18)F-labeling protocol.

Positron emission tomography molecular imaging for drug development

Human in vivo molecular imaging with positron emission tomography (PET) enables a new kind of 'precision pharmacology', able to address questions central to drug development. Biodistribution studies with drug molecules carrying positron-emitting radioisotopes can test whether a new chemical entity reaches a target tissue compartment (such as the brain) in sufficient amounts to be pharmacologically active. Competition studies, using a radioligand that binds to the target of therapeutic interest with adequate specificity, enable direct assessment of the relationship between drug plasma concentration and target occupancy. Tailored radiotracers can be used to measure relative rates of biological processes, while radioligands specific for tissue markers expected to change with treatment can provide specific pharmacodynamic information. Integrated application of PET and magnetic resonance imaging (MRI) methods allows molecular interactions to be related directly to anatomical or physiological changes in a tissue. Applications of imaging in early drug development can suggest approaches to patient stratification for a personalized medicine able to deliver higher value from a drug after approval. Although imaging experimental medicine adds complexity to early drug development and costs per patient are high, appropriate use can increase returns on R and D investment by improving early decision making to reduce new drug attrition in later stages. We urge that the potential value of a translational molecular imaging strategy be considered routinely and at the earliest stages of new drug development.

Synthesis of [11C]interleukin 8 using a cell-free translation system and l-[11C]methionine

Positron emission tomography (PET), which requires a compound labeled with a positron emitter radioisotope as an imaging probe, is one of the most useful and valuable imaging modalities in molecular imaging. It has several advantages over other imaging modalities, particularly in sensitive and quantitative investigations of molecular functions and processes in vivo. Recent advances in biopharmaceuticals development have increased interest in practical methods for proteins and peptides labeling with positron emitter radioisotope for PET molecular imaging. Here, we propose a novel approach for preparing positron emitter-labeled proteins and peptides based on biochemical synthesis using a reconstituted cell-free translation system. In this study, [(11)C]interleukin 8 (IL-8; MW 9.2 kDa) was successfully synthesized by the cell-free system in combination with l-[(11)C]methionine. The in vitro biochemical reaction proceeded smoothly and gave maximum radioactivity of [(11)C]IL-8 at 20 min with a radiochemical yield of 63%. Purification of [(11)C]IL-8 was achieved by conventional cation exchange and ultrafiltration methods, resulting in enough amount of radioactivity with excellent radiochemical purity (>95%) for small-animal imaging. This study clearly demonstrates that cell-free protein production system combined with positron emitter-labeled amino acid holds great promise as a novel approach to prepare radiolabeled proteins and peptides for PET imaging.

Radiopharmaceutical Chemistry with Iodine-124: A Non-Standard Radiohalogen for Positron Emission Tomography

Positron emission tomography (PET) is a powerful molecular imaging technology with the ability to image and monitor molecular events in vivo and in real time. With the increased application of PET radiopharmaceuticals for imaging physiological and pathological processes in vivo, there is a demand for versatile positron emitters with longer physical and biological half-lives. Traditional PET radionuclides, such as carbon-11 ((11)C) and fluorine-18 ((18)F), have relatively short half-lives (20 min and 110 min, respectively). Among the currently available positron emitters, the non-standard radiohalogen iodine-124 ((124)I) has the longest physical half-life at 4.2 d. This, combined with the well characterized radiochemistry of radioiodine, is contributing to the increasing utility of (124)I in investigating slow and complex pharmacokinetic processes in clinical nuclear medicine and small animal PET imaging studies. This review will summarize the progress to date on the potential of (124)I as a positron emitting nuclide for molecular imaging purposes, beginning with the production of (124)I. Particular emphasis will be placed on the basic radiochemistry as it applies to the production of various (124)I-labeled compounds, from small molecules, to biomolecules such as peptides and proteins, and finally to macromolecules like nanoparticles. The review will conclude by highlighting promising future directions in using (124)I as a positron emitter in PET radiochemistry and molecular imaging.

Recent Progress in Radiofluorination of Peptides for PET Molecular Imaging

Because of its low positron energy, lack of side emission, and a moderate half-life, Fluorine-18 (β+, 0.635 MeV [97%], t1/2 = 109.8 min) has ideal physical properties for positron emission tomography (PET). With the increasing numbers of peptides that are potentially applicable for molecular imaging of diseases, novel and simple 18F-labeling methods have been actively investigated and reported. In this review, a few well established and widely-used radiofluorination strategies are discussed. Novel approaches including click chemistry, one-step chelation labeling (i.e. Al18F-NOTA), and silicon-based 18F labeling are described as well. Keywords: 18F, Radiofluorination, Positron emission tomography, Peptide, Molecular Imaging, SPECT, chelation labeling, click reaction, HPLC