Radiolabeled peptides for tumor imaging with PET that can be produced with kits are currently in the spotlight of radiopharmacy and nuclear medicine. The diagnosis of neuroendocrine tumors in particular has been a prime example for the usefulness of peptides labeled with a variety of different radionuclides. Among those, 68 Ga and 18 F stand out because of the ease of radionuclide introduction (e.g., 68 Ga isotope) or optimal nuclide properties for PET imaging (slightly favoring the 18 F isotope). The in vivo properties of good manufacturing practice-compliant, newly developed kitlike-producible 18 F-SiFA-and 18 F-SiFAlin-(SiFA 5 silicon-fluoride acceptor) modified TATE derivatives were compared with the current clinical gold standard 68 Ga-DOTATATE for high-quality imaging of somatostatin receptor-bearing tumors. Methods: SiFA-and SiFAlin-derivatized somatostatin analogs were synthesized and radiolabeled using cartridge-based dried 18 F and purified via a C18 cartridge (radiochemical yield 49.8% ± 5.9% within 20-25 min) without high-performance liquid chromatography purification. Tracer lipophilicity and stability in human serum were tested in vitro. Competitive receptor binding affinity studies were performed using AR42J cells. The most promising tracers were evaluated in vivo in an AR42J xenograft mouse model by ex vivo biodistribution and in vivo PET/CT imaging studies for evaluation of their pharmacokinetic profiles, and the results were compared with those of the current clinical gold standard 68 Ga-DOTATATE. Results: Synthetically easily accessible 18 F-labeled silicon-fluoride acceptor-modified somatostatin analogs were developed. They exhibited high binding affinities to somatostatin receptor-positive tumor cells (1.88-14.82 nM). The most potent compound demonstrated comparable pharmacokinetics and an even slightly higher absolute tumor accumulation level in ex vivo biodistribution studies as well as higher tumor standardized uptake values in PET/CT imaging than 68 Ga-DOTATATE in vivo. The radioactivity uptake in nontumor tissue was higher than for 68 Ga-DOTATATE. Conclusion: The introduction of the novel SiFA building block SiFAlin and of hydrophilic auxiliaries enables a favorable in vivo biodistribution profile of the modified TATE peptides, resulting in high tumorto-background ratios although lower than those observed with 68 Ga-DOTATATE. As further advantage, the SiFA methodology enables a kitlike labeling procedure for 18 F-labeled peptides advantageous for routine clinical application.

The dynamic and multicellular processes of neuroinflammation are mediated by the nonneuronal cells of the central nervous system, which include astrocytes and the brain’s resident macrophages, microglia. Although initiation of an inflammatory response may be beneficial in response to injury of the nervous system, chronic or maladaptive neuroinflammation can have harmful outcomes in many neurological diseases. An acute neuroinflammatory response is protective when activated neuroglia facilitate tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. On the other hand, chronic neuroglial activation is a major pathological mechanism in neurodegenerative diseases, likely contributing to neuronal dysfunction, injury, and disease progression. Therefore, the development of specific and sensitive probes for positron emission tomography (PET) studies of neuroinflammation is attracting immense scientific and clinical interest. An early phase of this research emphasized PET studies of the prototypical imaging biomarker of glial activation, translocator protein-18 kDa (TSPO), which presents difficulties for quantitation and lacks absolute cellular specificity. Many alternate molecular targets present themselves for PET imaging of neuroinflammation in vivo, including enzymes, intracellular signaling molecules as well as ionotropic, G-protein coupled, and immunoglobulin receptors. We now review the lead structures in radiotracer development for PET studies of neuroinflammation targets for neurodegenerative diseases extending beyond TSPO, including glycogen synthase kinase 3, monoamine oxidase-B, reactive oxygen species, imidazoline-2 binding sites, cyclooxygenase, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, cannabinoid-2 receptor, the chemokine receptor CX3CR1, purinergic receptors: P2X7 and P2Y12, the receptor for advanced glycation end products, Mer tyrosine kinase, and triggering receptor expressed on myeloid cells-1. We provide a brief overview of the cellular expression and function of these targets, noting their selectivity for astrocytes and/or microglia, and highlight the classes of PET radiotracers that have been investigated in early-stage preclinical or clinical research studies of neuroinflammation.

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Straightforward radiosynthesis protocols for F-labeled radiopharmaceuticals are an indispensable but often overlooked prerequisite to successfully perform molecular imaging studies in vivo by PET. In recent years, thanks to the expansion of theF chemical toolbox, structurally diverse and novel clinically relevant radiopharmaceuticals have been synthesized with both high efficiency and ready implementation. This article provides an overview of recent F-labeling methodologies, specifically for B-F, Si-F, Al-F, and iodine (III)-mediated radiofluorination via the spirocyclic iodonium ylide technology.

Unorthodox (18)F-labeling strategies not employing the formation of a carbon-(18)F bond are seldom found in radiochemistry. Historically, the formation of a boron- or silicon-(18)F bond has been introduced very early on into the repertoire of labeling chemistries, but is without translation into any clinical radiotracer besides inorganic B[(18)F]F4(-) for brain tumor diagnosis. For many decades these labeling methodologies were forgotten and have just recently been revived by a handful of researchers thinking outside the box. When breaking with established paradigms such as the inability to obtain labeled compounds of high specific activity via isotopic exchange or performing radiofluorination in aqueous media, the research community often reacts skeptically. In 2005 and 2006, two novel labeling methodologies were introduced into radiochemistry for positron emission tomography (PET) tracer development: RBF3(-) labeling reported by Perrin et al. and the SiFA methodology by Schirrmacher, Jurkschat, and Waengler et al. which is based on isotopic exchange (IE). Both labeling methodologies have been complemented by other noncanonical strategies to introduce (18)F into biomolecules of diagnostic importance, thus profoundly enriching the landscape of (18)F radiolabeling. B- and Si-based labeling strategies finally revealed that IE is a viable alternative to established and traditional radiochemistry with the advantage of simplifying both the labeling effort as well as the necessary purification of the radiotracer. Hence IE will be the focus of this contribution over other noncanonical labeling methods. Peptides for tumor imaging especially lend themselves favorably toward one-step labeling via IE, but small molecules have been described as well, taking advantage of these new approaches, and have been used successfully for brain imaging. This Review gives an account of both radiochemistries centered on boron and silicon, describing the very beginnings of their basic research, the path that led to optimization of their chemistries, and the first encouraging preclinical results paving the way to their clinical use. This side by side approach will give the reader the opportunity to follow the development of a new basic discovery into a clinically applicable radiotracer including all the hurdles that have had to be overcome.

In this paper, we describe the use of Cu-mediated [ F]fluorodeboronation for the automated production of positron emission tomography radiotracers suitable for clinical use. Two recurrent issues with the method, low radiochemical conversion on automation and protoarene byproduct purification issues, have been successfully addressed. The new method was utilized to produce sterile injectable doses of [ F]-(±)-IPMICF17, a positron emission tomography radiotracer for tropomyosin receptor kinase B/C, using an automated synthesis module. The product was isolated in 1.9 ± 0.1% isolated radiochemical yield, excellent radiochemical purity (>99%), and high specific activity (5294 ± 1227 Ci/mmol). Quality control testing confirmed that doses were suitable for clinical use.

Background. Over the recent years, radiopharmaceutical chemistry has experienced a wide variety of innovative pushes towards finding both novel and unconventional radiochemical methods to introduce fluorine-18 into radiotracers for positron emission tomography (PET). These “nonclassical” labeling methodologies based on silicon-, boron-, and aluminium-18F chemistry deviate from commonplace bonding of an [18F]fluorine atom (18F) to either an aliphatic or aromatic carbon atom. One method in particular, the silicon-fluoride-acceptor isotopic exchange (SiFA-IE) approach, invalidates a dogma in radiochemistry that has been widely accepted for many years: the inability to obtain radiopharmaceuticals of high specific activity (SA) via simple IE. Methodology. The most advantageous feature of IE labeling in general is that labeling precursor and labeled radiotracer are chemically identical, eliminating the need to separate the radiotracer from its precursor. SiFA-IE chemistry proceeds in dipolar aprotic solvents at room temperature and below, entirely avoiding the formation of radioactive side products during the IE. Scope of Review. A great plethora of different SiFA species have been reported in the literature ranging from small prosthetic groups and other compounds of low molecular weight to labeled peptides and most recently affibody molecules. Conclusions. The literature over the last years (from 2006 to 2014) shows unambiguously that SiFA-IE and other silicon-based fluoride acceptor strategies relying on 18F− leaving group substitutions have the potential to become a valuable addition to radiochemistry.

Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, [3H]PF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer’s disease (AD), suggesting application for these compounds in AD diagnosis and identified [11C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3β-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC50 = 0.030 nM) and selective (>10-fold GSK-3β/GSK-3α) GSK-3β inhibitor known to date. Inhibition of CRMP2T514 and tau phosphorylation, as well as favorable therapeutic window against WNT/β-catenin signaling activation, was observed in cells.