Current Topics in Medicinal Chemistry - Volume 10, Issue 16, 2010

Medicinal radiochemistry involves design, synthesis and evaluation of radiotracers for emission tomography imaging. The development of new radiotracers is based on the structure-imaging properties relationships, suitability for radiolabeling and safety properties. Medicinal radiochemistry emerged over the last three decades mainly as a result of the rapid advances in positron-emission tomography (PET) and single photon emission computed tomography (SPECT). Nowadays most medicinal chemistry journals publish PET radiochemistry papers and there are also a number of specialized journals available. Initially we planned to publish a single special issue in 2010 on recent advances in the development of in vivo radiotracers, but, because the enthusiastic response of the authors substantially exceeded the space of a single issue, we divided the articles between two issues. In special issue # 15 entitled “Recent advances in the medicinal radiochemistry of radioligands for cerebral in vivo imaging” there is a discussion of positron emission tomography radioligands for several receptors of central nervous system. In special issue # 16 entitled “Current topics in the development of radioligands for positron-emission tomography imaging”, recent progress in the radioprobes for in vivo imaging of various non-central targets and advances in synthetic methodologies of PET radioligands is presented. Current Topics in the Development of Radioligands for Positron-Emission Tomography Imaging The paper from Mathews and Szabo presents the current status of PET radioligands for imaging of the angiotensin II subtype 1 receptor (AT1R). These radioligands may be vital to the development of more potent and specific drugs for the treatment of hypertension. Imaging studies using radiolabeled AT1R ligands have revealed the role of AT1R in angiogenesis as well as in various disease states beyond hypertension. In the next four reviews, progress in radioprobe development for imaging of cancer is presented. The paper from Mease reviews radionuclide based imaging agents for planar, single photon emission computed tomography (SPECT), and positron emission tomography (PET) imaging currently used in the clinic and those under development for prostate cancer. Alauddin et al. summarizes the present status of radiolabeled nucleoside analogues for PET imaging of HSV1-tk gene expression which is important for optimization of the clinical gene therapy protocols. The article by Roesch and Riss provides a very comprehensive overview of development of 68Ga-labeled PET agents for broad cancer imaging applications with emphasis on the 68Ge/68Ga generator systems. Another important aspect of PET radiochemistry for tumor imaging is reviewed in the Olberg's and Hjelstuen's paper that describes labeling strategies of peptides with 18F. The latest synthetic methods of 18F-labeled peptides may be a basis for preparation of the previously not available radioimaging probes. The last article of this issue written by Roeda and Dollé highlights the radiochemistry of [11C]phosgene, an important synthon for a number of PET radiochemistry applications including of synthesis of 11C-labeled carbamates, carbonates, heterocycles and C-11C-bond formation.

Over the last years, ligands for angiotensin II subtype 1 receptor (AT1R) have been developed as an alternative to the use of angiotensin-converting enzyme (ACE) inhibitors for controlling high blood pressure. Radiolabeled versions of these ligands have proven vital to the development of more potent and specific drugs for the treatment of hypertension. Imaging studies using radiolabeled AT1R ligands have also elucidated the role these receptors play in angiogenesis as well as in various disease states beyond hypertension.

Prostate cancer (PCa) is the second leading cause of cancer deaths in American men. Early detection of PCa by blood tests for elevated levels of prostate-specific-antigen (PSA) has lead to early treatment and a reduction in death rates. However, PSA level alone does not distinguish between PCa and normal conditions that cause elevated PSA. Furthermore, because PCa can be a very slow growing cancer, even confirmation of PCa cells in a biopsy gives no indication whether the PCa will progress into active disease within the individual's lifetime. As a result many patients receive treatment that they may not need. Imaging is an attractive modality for the detection and characterization of disease because most techniques are non- or minimally invasive, nondestructive, provide dynamic real-time data, and allow for repeat measurements. In PCa, advanced imaging techniques could be useful for accurate staging of primary disease, restaging of recurrent disease, detection of metastatic lesions, and predicting the aggressiveness of the disease. This paper reviews the radionuclide based imaging agents for planar, single photon emission computed tomography (SPECT), and positron emission tomography (PET) imaging currently used in the clinic and those under development for PCa. The former includes the bone agents technetium diphosphonates and F-18 fluoride, the metabolic agents 2-[18F]fluoro-2-deoxy-D-glucose (FDG), and receptor targeted radiolabeled monoclonal antibodies including ProstaScint. The latter agents include C-11 acetate, C-11 and F-18 choline, C-11 and F-18 labeled 1-aminocyclobutane-1-carboxylic acid, radiolabeled androgen receptor binding compounds, radiolabeled peptides and small molecules for receptors over expressed either on prostate cancer itself or on the associated tumor neovasculature. Coregistration of PET or SPECT images with CT or MRI scans, improvements in imaging cameras, and image reconstruction algorithms have improved the quality of the images to the point where dual modality (radionuclide/CT or MRI) imaging with several agents can now be considered for staging of PCa. In addition, the high selectivity and rapid localization of many of the new agents under development portends promise for a greater use of radionuclide imaging for prostate cancer detection, characterization, and treatment monitoring.

The HSV1-tk gene has been explored as a reporter and/or suicide gene in molecular imaging of gene expression. Gene therapy with HSV1-tk and the use of this gene as a marker have been applied in patients with various forms of cancer. However, the conditions for clinical gene therapy protocols have yet to be optimized. A method to monitor the activity of HSV1-tk in vivo would be extremely useful to optimize clinical gene therapy protocols. Positron emission tomography (PET) with a suitable probe can offer information about both the extent of gene expression and its distribution, provided that an appropriate reporter gene is included in the therapeutic cassette. PET imaging provides higher resolution and sensitivity and allows noninvasive quantification of biological processes. Several radiolabeled pyrimidine (thymidine) and purine (acycloguanosine) derivatives have been developed as reporter probes for imaging of HSV1-TK enzyme activity with PET. In this review, information on radiolabeling and PET imaging of HSV1-tk gene expression with various nucleoside analogues is presented.

68Ge/68Ga radionuclide generators have been investigated for almost fifty years now, since the cyclotronindependent availability of positron emitting 68Ga via the 68Ge/68Ga system had always attracted researches working in basic nuclear chemistry as well as radiopharmaceutical chemistry. However, it took decades and generations of research (and researchers) to finally approach a reliable level of 68Ge/68Ga generator designs, adequate to the modern requirements of radiometal labeling chemistry. 68Ga radiopharmacy now is awaking from a sort of hibernation. The exciting perspective for the 68Ge/68Ga generator, now - more than ever, asks for systematic chemical, radiochemical, technological and radiopharmaceutical efforts, to guarantee reliable, highly-efficient and medically approved 68Ge/68Ga generator systems. The expected future broad clinical impact of 68Ga-labelled radiopharmaceuticals - beyond the 68Ga-DOTA-octreotide derivatives - for imaging tumors and many organs, on the other hand, identifies the development of sophisticated GaIII chelating structures to be a key factor. Today, open chain complexing agents have almost completely been displaced by macrocyclic DOTA and NOTA-derived conjugates. Structures of chelating moieties are being optimized in terms of thermodynamic stability and kinetic inertness, in terms of labeling efficacies at different, even acidic pH, and in terms of synthetic options towards bifunctionality, directed to sophisticated covalent coupling strategies to a variety of biologically relevant targeting vectors. Today, one may expect that the 68Ge/68Ga radionuclide generator systems could contribute to and facilitate the clinical impact of nuclear medicine diagnoses for PET in a dimension comparable to the established 99Mo/99mTc generator system for SPECT.

A variety of peptides labeled with the positron emitting radionuclide fluorine-18 have shown promise as tracers for use in positron emission tomography (PET) for the detection of malignancies. Peptides can be produced with a formidable versatility allowing them to target a vast diversity of uniquely expressed or overexpressed receptors associated with pathological conditions. The quantitative nature of PET gives the opportunity to stage and monitor the progress of the disease. The pharmacokinetics of peptides are compatible with the half-life of fluorine-18 (110 min), allowing the generation of high quality PET images within the time frame of 1-3 hours or longer. The production of high energy gamma emitting radiopharmaceuticals puts certain constraints and requirements on the production method. These are to a large extent dictated by the short half-life of the 18F and the need for appropriate shielding of the operator. For large scale productions, a fully automated production process is a requirement. Compared to low molecular weight fluorine-18 labeled tracers, the production of 18F-labeled peptides entails specific challenges. As opposed to small organic molecules where direct labeling with no-carrier added 18-fluoride is feasible, peptides do not normally allow for such a direct labeling approach. Therefore, peptides are for all practical purposes labeled by 18F-prosthetic groups, also called bifunctional labeling agents, making their synthesis relatively complicated. During the last decade, various methodologies have been developed for the introduction of 18F-fluoride into peptides. The strategies employed for the labeling of peptides with 18F all represent their own advantages and inconveniences, still some are more flexible than others. In this review, the aim is to provide an overview and discuss the strategies currently used for labeling of peptides with 18F for PET.

[11C]Phosgene has been playing a relatively modest but continuous and manifest role all along the history of radiochemistry for Positron Emission Tomography. It acts as a radiolabelling agent through carbonyl insertion, usually between heteroatoms, and benefits from a high chemical reactivity allowing for short reaction times. The aim of this review is to give an overview of this radiochemistry from its beginning until the present day. After drawing up the inventory of the various ways of its production, the reactions in which it has been employed and the labelled products that have been synthesised with it are catalogued. This comprises the reactions of [11C]phosgene with primary, secondary and tertiary amines to labelled isocyanates and carbamoyl chlorides, which serve as intermediates for symmetrical and unsymmetrical [11C]ureas and [11C]carbamates, reactions with alcohols leading to labelled carbamates and carbonates via [11C]chloroformates, cyclisation reactions to heterocycles and the radiochemistry of the secondary radiolabelling agents [11C]urea and diethyl- or dimethyl [11C]carbonate. Apart from this already vast field of chemical possibilities there should be room for extension of the use of [11C]phosgene to other chemistry, notably that of C-11C bond formation.