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Arginase is a widely known enzyme of the urea cycle that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. The action of arginase goes beyond the boundaries of hepatic ureogenic function, being widespread through most tissues. Two arginase isoforms coexist, the type I (Arg1) predominantly expressed in the liver and the type II (Arg2) expressed throughout extrahepatic tissues. By producing L-ornithine while competing with nitric oxide synthase (NOS) for the same substrate (L-arginine), arginase can influence the endogenous levels of polyamines, proline, and NO•. Several pathophysiological processes may deregulate arginase/NOS balance, disturbing the homeostasis and functionality of the organism. Upregulated arginase expression is associated with several pathological processes that can range from cardiovascular, immune-mediated, and tumorigenic conditions to neurodegenerative disorders. Thus, arginase is a potential biomarker of disease progression and severity and has recently been the subject of research studies regarding the therapeutic efficacy of arginase inhibitors. This review gives a comprehensive overview of the pathophysiological role of arginase and the current state of development of arginase inhibitors, discussing the potential of arginase as a molecular imaging biomarker and stimulating the development of novel specific and high-affinity arginase imaging probes.

There is an unmet need for late-stage 18F-fluorination strategies to label molecules with a wide range of relevant functionalities to medicinal chemistry, in particular (hetero)arenes, aiming to obtain unique in vivo information on the pharmacokinetics/pharmacodynamics (PK/PD) using positron emission tomography (PET). In the last few years, Cu-mediated oxidative radiofluorination of arylboronic esters/acids arose and has been successful in small molecules containing relatively simple (hetero)aromatic groups. However, this technique is sparsely used in the radiosynthesis of clinically significant molecules containing more complex backbones with several aromatic motifs. In this work, we add a new entry to this very limited database by presenting our recent results on the 18F-fluorination of an arylboronic ester derivative of atorvastatin. The moderate average conversion of [18F]F− (12%), in line with what has been reported for similarly complex molecules, stressed an overview through the literature to understand the radiolabeling variables and limitations preventing consistently higher yields. Nevertheless, the current disparity of procedures reported still hampers a consensual and conclusive output.

The dopaminergic system plays a major role in neurological and psychiatric disorders such as Parkinsons disease, Huntingtons disease, tardive dyskinea and schizophrenia. Knowledge on altered dopamine synthesis, receptor densities and status are important for understanding the mechanisms underlying the pathogenesis and therapy of diseases. PET provides a non-invasive tool to investigate these features in vivo, provided the availability of suitable radiopharmaceuticals. To investigate presynaptic function, PET-tracers have been developed to measure dopamine synthesis and transport. For the former the most commonly used tracers are 6-[18F]FDOPA and 6-[18F]FMT, whereas for the latter several 11C/18F-labeled tropane analogues are being clinically used. Postsynaptically, dopamine exerts actions through several subtypes of the dopamine receptor. The dopamine receptor family consists of 5 subtypes D1-D5. In order to investigate the role of each receptor subtype, selective and high-affinity PETradioligands are required. For the dopamine D1-subtype the most commonly used ligand is [11C]SCH 23390 or [11C]NNC 112, whereas for the D2/D3-subtype [11C]raclopride is a common tracer. [18 F]Fallypride is a suitable PET-tracer for the investigation of extrapyramidal D2-receptors. For the other subtypes no suitable radioligands have been developed yet. This paper gives an overview of the current status on dopamine PET-tracers and the development of new lead compounds as potential PET-tracers by medicinal chemistry.

Adenosine and dopamine interact antagonistically in living mammals. These interactions are mediated via adenosine A2A and dopamine D2 receptors (R). Stimulation of A2AR inhibits and blockade of A2AR enhances D2R-mediated locomotor activation and goal-directed behavior in rodents. In striatal membrane preparations, adenosine decreases both the affinity and the signal transduction of D2R via its interaction with A2AR. Reciprocal A2AR/D2R interactions occur mainly in striatopallidal GABAergic medium spiny neurons (MSNs) of the indirect pathway that are involved in motor control, and in striatal astrocytes. In the nucleus accumbens, they also take place in MSNs involved in reward-related behavior. A2AR and D2R co-aggregate, co-internalize, and co-desensitize. They are at very close distance in biomembranes and form heteromers. Antagonistic interactions between adenosine and dopamine are (at least partially) caused by allosteric receptor–receptor interactions within A2AR/D2R heteromeric complexes. Such interactions may be exploited in novel strategies for the treatment of Parkinson’s disease, schizophrenia, substance abuse, and perhaps also attention deficit-hyperactivity disorder. Little is known about shifting A2AR/D2R heteromer/homodimer equilibria in the brain. Positron emission tomography with suitable ligands may provide in vivo information about receptor crosstalk in the living organism. Some experimental approaches, and strategies for the design of novel imaging agents (e.g., heterobivalent ligands) are proposed in this review.

This document is intended as a supplement to the EANM “Guidelines on current Good Radiopharmacy Practice (cGRPP)” issued by the Radiopharmacy Committee of the EANM (Gillings et al. in EJNMMI Radiopharm Chem. 6:8, 2021 ). The aim of the EANM Radiopharmacy Committee is to provide a document that describes how to manage risks associated with small-scale “in-house” preparation of radiopharmaceuticals, not intended for commercial purposes or distribution.

FDG, the most common radiopharmaceutical for PET imaging in oncology, is not tumor-specific. Significant tracer accumulation can also occur in viral, bacterial and fungal infections, in other forms of inflammatory tissue and in brown fat. FDG accumulation in inflammatory tissue may cause false positives during cancer screening and false classification as a nonresponder during drug treatment. Yet, discrimination between benign and malignant processes is often possible when the kinetics of FDG uptake is taken into account (e.g., by delayed, dual or dynamic PET imaging). Other PET tracers which are considered as proliferation markers may allow an improved differential diagnosis of tumor and inflammation. These include lipid precursors, amino acids, nucleosides and receptor ligands. Strictly speaking, only labelled nucleosides which are incorporated into DNA (e.g. 2- C-thymidine, Br-bromofluorodeoxyuridine, C-FMAU) are true proliferation markers, but the tissue kinetics of radiopharmaceuticals tracing amino acid transport, membrane metabolism, enzyme activity or receptor expression can be a surrogate marker of cellular proliferation if the activity of such processes is increased in rapidly dividing cells. Well-known imaging targets for oncology are: (i) glucose transport ( F-FDG); (ii) choline kinase activity ( C-choline); (iii) amino acid transport (11C-methionine); and (iv) activity of thymidine kinase 1 ( F-FLT). Radiolabeled choline, amino acids and nucleosides have been reported to show greater tumor-specificity than 18F-FDG, both in experimental animals and in humans. However, the specificity of such tracers is not absolute. 11C-choline is strongly accumulated in bacterial infections and sterile inflammation. 11C-Methionine can show high uptake in brain abscesses. F-FLT is taken up in non-metastatic reactive lymph nodes because of reactive B-lymphocyte proliferation. Moreover, FLT-PET cannot distinguish between benign lesions showing blood-brain barrier disruption and malignant brain tumors. Although proliferation is a key factor of malignancy, cell division can also occur in benign processes, including some forms of infection and inflammation. Because of such limitations, the tumor specificity of PET will never reach 100%. Each radiolabeled proliferation marker (or surrogate marker of proliferation) has high physiological uptake in some areas of the body and the tumor uptake of these radiopharmaceuticals is often lower than that of FDG. Proliferation markers should therefore not be considered as replacements of FDG, but rather as useful additions to the imaging arsenal which can provide additional diagnostic specificity and biological information for treatment planning and response monitoring.

This guideline on molar activity (Am) and specific activity (As) focusses on small molecules, peptides and macromolecules radiolabelled for diagnostic and therapeutic applications. In this guideline we describe the definition of Am and As, and how these measurements must be standardised and harmonised. Selected examples highlighting the importance of Am and As in imaging studies of saturable binding sites will be given, and the necessity of using appropriate materials and equipment will be discussed. Furthermore, common Am pitfalls and remedies are described. Finally, some aspects of Am in relation the emergence of a new generation of highly sensitive PET scanners will be discussed.

Imaging techniques, such as positron emission tomography (PET), represent great progress in the clinical development of drugs and diagnostics. However, the efficient and timely synthesis of appropriately labeled compounds is a largely unsolved problem. Numerous small drug-like molecules with high structural diversity can be synthesized via convergent multicomponent reactions (MCRs). The combination of PET labeling with MCR synthesis of biologically active compounds can greatly simplify radioanalytical and imaging-based analysis. In a proof-of-concept study, we optimized robust on-site radiolabeling conditions that were subsequently applied to several structurally different drug-like MCR scaffolds (e.g., arenes, β-lactam, tetrazole, and oxazole). These labeled scaffolds were synthesized via pinacol-derived aryl boronic esters (arylBPin) by copper-mediated oxidative 18F-fluorination with radiochemical conversions (RCCs) from 15% to 76%.