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Recent progress realized in the development of optical imaging (OPI) probes and devices has made this technique more and more affordable for imaging studies and fluorescence-guided surgery procedures. However, this imaging modality still suffers from a low depth of penetration, thus limiting its use to shallow tissues or endoscopy-based procedures. In contrast, positron emission tomography (PET) presents a high depth of penetration and the resulting signal is less attenuated, allowing for imaging in-depth tissues. Thus, association of these imaging techniques has the potential to push back the limits of each single modality. Recently, several research groups have been involved in the development of radiolabeled fluorophores with the aim of affording dual-mode PET/OPI probes used in preclinical imaging studies of diverse pathological conditions such as cancer, Alzheimer’s disease, or cardiovascular diseases. Among all the available PET-active radionuclides, 18F stands out as the most widely used for clinical imaging thanks to its advantageous characteristics (t1/2 = 109.77 min; 97% β+ emitter). This review focuses on the recent efforts in the synthesis and radiofluorination of fluorescent scaffolds such as 4,4-difluoro-4-bora-diazaindacenes (BODIPYs), cyanines, and xanthene derivatives and their use in preclinical imaging studies using both PET and OPI technologies.

Rapid synthesis of nanomaterials in scalable quantities is critical for accelerating the discovery and commercial translation of nanoscale-based technologies. The synthesis of metal nanogold and silver in volumes larger than 100 mL is not automatized and might require of the use of harsh conditions that in most cases is detrimental for the production of nanoparticles with reproducible size distributions. In this work, we present the development and optimization of an open-access low-cost NanoParticle Flow Synthesis System (NPFloSS) that allows for the rapid preparation of volumes of up to 1 L of gold and silver nanoparticle aqueous solutions.

Non-activated (electron-rich and/or sterically hindered) arenes are prevalent chemical scaffolds in pharmaceuticals and positron emission tomography (PET) diagnostics. Despite substantial efforts to develop a general method to introduce 18 F into these moieties for molecular imaging by PET, there is an urgent and unmet need for novel radiofluorination strategies that result in sufficiently labeled tracers to enable human imaging. Herein, we describe an efficient method that relies on spirocyclic iodonium ylide (SCIDY) precursors for one-step and regioselective radiofluorination, as well as proof-of-concept translation to the radiosynthesis of a clinically useful PET tracer, 3-[ 18 F]fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ([ 18 F]FPEB). The protocol begins with the preparation of a SCIDY precursor for FPEB, followed by radiosynthesis of [ 18 F]FPEB, by either manual operation or an automated synthesis module. [ 18 F]FPEB can be obtained in quantities >7.4 GBq (200 mCi), ready for injection (20 ± 5%, non–decay corrected), and has excellent chemical and radiochemical purity (>98%) as well as high molar activity (666 ± 51.8 GBq/μmol; 18 ± 1.4 Ci/μmol). The total time for the synthesis and purification of the corresponding labeling SCIDY precursor is 10 h. The subsequent radionuclide production, experimental setup, 18 F labeling, and formulation of a product that is ready for injection require 2 h. 18 F labeling of non-activated arenes (e.g., 3-[ 18 F]fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ([ 18 F]FPEB)) is an unmet need for PET imaging. This protocol uses a spirocyclic iodonium ylide method for one-step, regioselective radiofluorination.

Fluorine-18 ( t ½ =109.7 min) is the most commonly used isotope to prepare radiopharmaceuticals for molecular imaging by positron emission tomography (PET). Nucleophilic aromatic substitution reactions of suitably activated (electron-deficient) aromatic substrates with no-carrier-added [ 18 F]fluoride ion are routinely carried out in the synthesis of radiotracers in high specific activities. Despite extensive efforts to develop a general 18 F-labelling technique for non-activated arenes there is an urgent and unmet need to achieve this goal. Here we describe an effective solution that relies on the chemistry of spirocyclic hypervalent iodine(III) complexes, which serve as precursors for rapid, one-step regioselective radiofluorination with [ 18 F]fluoride. This methodology proves to be efficient for radiolabelling a diverse range of non-activated functionalized arenes and heteroarenes, including arene substrates bearing electron-donating groups, bulky ortho functionalities, benzylic substituents and meta -substituted electron-withdrawing groups. Polyfunctional molecules and a range of previously elusive 18 F-labelled building blocks, compounds and radiopharmaceuticals are synthesized. Fluorine-18 containing molecules are important for PET imaging, but due to the short half-life it is necessary to develop rapid methods for its introduction. Here, the authors use spirocyclic iodine(III) precursors, allowing direct 18F labelling of highly functionalized non-activated arenes and PET radiopharmaceuticals.

The isotopic labelling of small molecules is integral to drug development and for understanding biochemical processes. The preparation of carbon-labelled α-amino acids remains difficult and time consuming, with established methods involving label incorporation at an early stage of synthesis. This explains the high cost and scarcity of C-labelled products and presents a major challenge in 11 C applications ( 11 C t 1/2  = 20 min). Here we report that aldehydes catalyse the isotopic carboxylate exchange of native α-amino acids with *CO 2 (* = 14, 13, 11). Proteinogenic α-amino acids and many non-natural variants containing diverse functional groups undergo labelling. The reaction probably proceeds via the trapping of *CO 2 by imine-carboxylate intermediates to generate iminomalonates that are prone to monodecarboxylation. Tempering catalyst electrophilicity was key to preventing irreversible aldehyde consumption. The pre-generation of the imine carboxylate intermediate allows for the rapid and late-stage 11 C-radiolabelling of α-amino acids in the presence of [ 11 C]CO 2 . Carbon-labelled α-amino acids are valuable compounds in drug development and nuclear medicine, but are difficult and time consuming to prepare. Now, an aldehyde-catalysed method has been developed for the direct C1-labelling of α-amino acids using *CO 2 (* = 14, 13, 11), providing access to many proteinogenic and non-natural labelled α-amino acids.

Isotopically carbon-labeled α-amino acids are valuable synthetic targets that are increasingly needed in pharmacology and medical imaging. Existing preparations rely on early stage introduction of the isotopic label, which leads to prohibitive synthetic costs and time-intensive preparations. Here we describe a protocol for the preparation of C1-labeled α-amino acids using simple aldehyde catalysts in conjunction with [*C]CO 2 (* = 14, 13, 11). This late-stage labeling strategy is enabled by the one-pot carboxylate exchange of unprotected α-amino acids with [*C]CO 2 . The protocol consists of three separate procedures, describing the syntheses of (±)-[1- 13 C]phenylalanine, (±)-[1- 11 C]phenylalanine and (±)-[1- 14 C]phenylalanine from unlabeled phenylalanine. Although the delivery of [*C]CO 2 is operationally distinct for each experiment, each procedure relies on the same fundamental chemistry and can be executed by heating the reaction components at 50–90 °C under basic conditions in dimethylsulfoxide. Performed on scales of up to 0.5 mmol, this methodology is amenable to C1-labeling of many proteinogenic α-amino acids and nonnatural derivatives, which is a breakthrough from existing methods. The synthesis of (±)-[1- 13 C]phenylalanine requires ~2 d, with product typically obtained in a 60–80% isolated yield ( n = 3, μ = 71, σ = 8.3) with an isotopic incorporation of 70–88% ( n = 18, μ = 72, σ = 9.0). Starting from the preformed imino acid (~3 h preparation time), rapid synthesis of (±)-[1- 11 C]phenylalanine can be completed in ~1 h with an isolated radiochemical yield of 13%. Finally, (±)-[1- 14 C]phenylalanine can be accessed in ~2 d with a 51% isolated yield and 11% radiochemical yield. Key points Amino acids can be labeled with carbon isotopes via carboxylate exchange using [*C]CO 2 where *C is either 13 C, 11 C or 14 C. Three procedures are described using phenylalanine as the example starting material; the main differences relate to the sources of [*C]CO 2 and how it is delivered. The products can be used immediately after a straightforward HPLC separation. Isotopically labeled amino acids are useful in pharmacology and for medical imaging. In this protocol, C1-labeled α-amino acids are prepared via late-stage carboxylate exchange of unprotected α-amino acids with [*C]CO 2 where *C is 13 C, 11 C or 14 C.

In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·µmol−1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 ± 0.08% ID/cc (percent of injected dose per cubic centimeter) at peak, 15–60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg·kg−1, i.p.), whole brain radioactivity uptake was diminished by 25%–40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned.

Activation of retinoid X receptors (RXRs) has been proposed as a therapeutic mechanism for the treatment of neurodegeneration, including Alzheimer's and Parkinson's diseases. We previously reported radiolabeling of a Food and Drug Administration-approved RXR agonist, bexarotene, by copper-mediated [11C]CO2 fixation and preliminary positron emission tomography (PET) neuroimaging that demonstrated brain permeability in nonhuman primate with regional binding distribution consistent with RXRs. In this study, the brain uptake and saturability of [11C]bexarotene were studied in rats and nonhuman primates by PET imaging under baseline and greater target occupancy conditions. [11C]Bexarotene displays a high proportion of nonsaturable uptake in the brain and is unsuitable for RXR occupancy measurements in the central nervous system.

Non-activated (electron-rich and/or sterically hindered) arenes are prevalent chemical scaffolds in pharmaceuticals and positron emission tomography (PET) diagnostics. Despite substantial efforts to develop a general method to introduce .sup.18F into these moieties for molecular imaging by PET, there is an urgent and unmet need for novel radiofluorination strategies that result in sufficiently labeled tracers to enable human imaging. Herein, we describe an efficient method that relies on spirocyclic iodonium ylide (SCIDY) precursors for one-step and regioselective radiofluorination, as well as proof-of-concept translation to the radiosynthesis of a clinically useful PET tracer, 3-[.sup.18F]fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ([.sup.18F]FPEB). The protocol begins with the preparation of a SCIDY precursor for FPEB, followed by radiosynthesis of [.sup.18F]FPEB, by either manual operation or an automated synthesis module. [.sup.18F]FPEB can be obtained in quantities >7.4 GBq (200 mCi), ready for injection (20 [plus or minus] 5%, non-decay corrected), and has excellent chemical and radiochemical purity (>98%) as well as high molar activity (666 [plus or minus] 51.8 GBq/[mu]mol; 18 [plus or minus] 1.4 Ci/[mu]mol). The total time for the synthesis and purification of the corresponding labeling SCIDY precursor is 10 h. The subsequent radionuclide production, experimental setup, .sup.18F labeling, and formulation of a product that is ready for injection require 2 h.