Search Results (13)

Background/Objectives: Leucine-rich repeat kinase 2 (LRRK2) is an enzyme implicated in Parkinson’s disease (PD) and a potential therapeutic target. LRRK2 PET radioligands could therefore function as imaging biomarkers for PD and as tools to measure enzyme occupancy of novel therapeutic candidates. This study aimed at developing novel radioligands for imaging using positron emission tomography (PET). Specific objectives were to synthesize fluorine-18-labeled pyrrolopyridine 1 ([¹⁸F]1), pyrrolo-pyrimidine 2 ([¹⁸F]2), as well as carbon-11-labeled pyrrolo-pyrimidine 3 ([¹¹C]3), and examine their binding specificity, using in vitro autoradiography (ARG) and in vivo positron emission tomography (PET) imaging in non-human primates (NHPs). Methods: Radiolabeling was achieved either by classical one-step fluorine-18 nucleophilic substitution reaction or by methylation using carbon-11 methane. [¹⁸F]1 and [¹⁸F]2 were tested in NHP and human whole-hemisphere ARG experiments. PET imaging was performed in cynomolgus monkeys. Radiometabolites were measured in monkey plasma using gradient HPLC. Results: The results demonstrated successful radiolabeling of all three ligands. In ARG studies, both [¹⁸F]1 and [¹⁸F]2 displayed binding in brain slices from NHP and human samples. The binding of [¹⁸F]1 was blocked by cold Compound 1 and structurally distinct Compound 3, but not by the structurally distinct LRRK2 inhibitor PFE-360. On the other hand, the binding of [¹⁸F]2 was blocked by PFE-360 in certain regions of the brain, indicating some level of specific binding to LRRK2. All three ligands showed relevant brain uptake (>3%ID), with highest uptake being observed for [¹⁸F]1, particularly in the thalamus. In contrast, brain uptake of [¹⁸F]2 and [¹¹C]3 was evenly distributed across all brain regions. No blocking effect of [¹⁸F]1 was observed after pretreatment with the structurally distinct LRRK2 inhibitors PFE-360 (0.5 mg/kg, iv) and GEN-7915 (40 mg/kg). Conclusions: PET imaging indicated a low in vivo specific binding of the radioligands in the cynomolgus monkey brain, suggesting that the radioligands are not suitable for LRRK2 imaging in vivo with PET. This study emphasizes the challenges in the development of PET radioligands for imaging LRRK2 and the need for additional work to achieve this goal. Full article

Astatine-211 (²¹¹At) has emerged as a promising radionuclide for targeted alpha therapy of cancer by virtue of its favorable nuclear properties. However, the limited in vivo stability of ²¹¹At-labeled radiopharmaceuticals remains a major challenge. This review provides a comprehensive overview of the current strategies for ²¹¹At radiolabeling, including nucleophilic and electrophilic substitution reactions, as well as the recent advances in the development of novel bifunctional coupling agents and labeling approaches to enhance the stability of ²¹¹At-labeled compounds. The preclinical and clinical applications of ²¹¹At-labeled radiopharmaceuticals, including small molecules, peptides, and antibodies, are also discussed. Looking forward, the identification of new molecular targets, the optimization of ²¹¹At production and quality control methods, and the continued evaluation of ²¹¹At-labeled radiopharmaceuticals in preclinical and clinical settings will be the key to realizing the full potential of ²¹¹At-based targeted alpha therapy. With the growing interest and investment in this field, ²¹¹At-labeled radiopharmaceuticals are poised to play an increasingly important role in future cancer treatment. Full article

The aim of this study was to measure the brain penetrance and kinetics of BIIB104, a first-in-class AMPA receptor potentiator developed for cognitive impairment associated with schizophrenia. It was recently halted in phase 2 clinical development, and there are a lack of tools to directly measure AMPA receptor engagement. To achieve this, the drug candidate was radiolabeled with carbon-11, and its brain penetrance and kinetics were measured in non-human primates via dynamic PET scans. Radiolabeling was achieved through a three-step nucleophilic [¹¹C]cyanation reaction in one pot, resulting in the high radioactivity and radiochemical purity (>99%) of [¹¹C]BIIB104. The study found that [¹¹C]BIIB104 entered the non-human primate brains at 4–5% ID at peak, with a homogeneous distribution. However, a mild regional heterogeneity was observed in the thalamus. The lack of conclusive evidence for a change in regional values after BIIB104 dosing suggests that any specific binding component of BIIB104 is negligible compared to the free and non-specific components in the living brain. Overall, the study demonstrated high brain uptake with minor variability in [¹¹C]BIIB104 distribution across various brain regions, its kinetics were consistent with those of passive diffusion, and the dominating components were the free concentration and non-specific binding. This information is valuable for understanding the potential effects and mechanisms of BIIB104 in the brain. Full article

Radiolabeled amino acids are an important class of agents for positron emission tomography imaging that target amino acid transporters in many tumor types. Traditional ¹⁸F-labeled amino acid synthesis strategies are always based on nucleophilic aromatic substitution reactions with multistep radiosynthesis and low radiochemical yields. In recent years, new ¹⁸F-labeling methodologies such as metal-catalyzed radiofluorination and heteroatom (B, P, S, Si, etc.)-¹⁸F bond formation are being effectively used to synthesize radiopharmaceuticals. This review focuses on recent advances in the synthesis, radiolabeling, and application of a series of ¹⁸F-labeled amino acid analogs using new ¹⁸F-labeling strategies. Full article

Nucleophilic ionic sources of fluoride are essential reagents in the synthetic toolbox to access high added-value fluorinated building blocks unattainable by other means. In this review, we provide a concise description and rationale of the outstanding features of one of these reagents, tetramethylammonium fluoride (TMAF), as well as disclosing the different methods for its preparation, and how its physicochemical properties and solvation effects in different solvents are intimately associated with its reactivity. Furthermore, herein we also comprehensively describe its historic and recent utilization, up to December 2021, in C-F bond-forming reactions with special emphasis on nucleophilic aromatic substitution fluorinations with a potential sustainable application in industrial settings, as well as its use as a base capable of rendering unprecedented transformations. Full article

The use of radiolabeled non-natural amino acids can provide high contrast SPECT/PET metabolic imaging of solid tumors. Among them, radiohalogenated tyrosine analogs (i.e., [¹²³I]IMT, [¹⁸F]FET, [¹⁸F]FDOPA, [¹²³I]8-iodo-L-TIC(OH), etc.) are of particular interest. While radioiodinated derivatives, such as [¹²³I]IMT, are easily available via electrophilic aromatic substitutions, the production of radiofluorinated aryl tyrosine analogs was a long-standing challenge for radiochemists before the development of innovative radiofluorination processes using arylboronate, arylstannane or iodoniums salts as precursors. Surprisingly, despite these methodological advances, no radiofluorinated analogs have been reported for [¹²³I]8-iodo-L-TIC(OH), a very promising radiotracer for SPECT imaging of prostatic tumors. This work describes a convenient synthetic pathway to obtain new radioiodinated and radiofluorinated derivatives of TIC(OH), as well as their non-radiolabeled counterparts. Using organotin compounds as key intermediates, [¹²⁵I]5-iodo-L-TIC(OH), [¹²⁵I]6-iodo-L-TIC(OH) and [¹²⁵I]8-iodo-L-TIC(OH) were efficiently prepared with good radiochemical yield (RCY, 51–78%), high radiochemical purity (RCP, >98%), molar activity (Am, >1.5–2.9 GBq/µmol) and enantiomeric excess (e.e. >99%). The corresponding [¹⁸F]fluoro-L-TIC(OH) derivatives were also successfully obtained by radiofluorination of the organotin precursors in the presence of tetrakis(pyridine)copper(II) triflate and nucleophilic [¹⁸F]F⁻ with 19–28% RCY d.c., high RCP (>98.9%), Am (20–107 GBq/µmol) and e.e. (>99%). Full article

Incorporation of [¹⁸F]fluorine into PET radiotracer structure has traditionally been accomplished via nucleophilic pathways. The [¹⁸F]fluoride is generated in an aqueous solution via proton irradiation of oxygen-18 enriched water and must to be introduced into water-free organic solutions in order to generate reactive species. Thus nucleophilic ¹⁸F-fluorination traditionally included steps for [¹⁸F]fluoride concentration on the anion exchange resin, followed by removal of residual water via azeotropic distillation with MeCN, a time-consuming process associated with radioactivity losses and difficult automation. To circumvent this, several adsorption/elution protocols were developed based on the minimization of water content in traditional kryptofix-based [¹⁸F]fluoride eluents. The use of pre-dried KOH/kryptofix solutions, tertiary alcohols, and strong organic bases was found to be effective. Advances in transition metal-mediated S_NAr approaches for radiolabeling of non-activated aromatic substrates have prompted development of alternative techniques for reactive [¹⁸F]fluoride species generation, such as organic solutions of non-basic alkyl ammonium and pyridinium sulfonates, etc. For radiofluorinations of iodonium salts precursors, a “minimalist” approach was introduced, avoiding the majority of pitfalls common to more complex methods. These innovations allowed the development of new time-efficient and convenient work-up procedures that are easily implementable in modern automated synthesizers. They will be the subject of this review. Full article

Introduction: Benzodiazepines, including temazepam are described as TSPO antagonists. In fact, TSPO was initially described as a peripheral benzodiazepine receptor (PBR) with a secondary binding site for diazepam. TSPO is a potential imaging target of neuroinflammation because there is an amplification of the expression of this receptor. Objectives: Herein, we developed a novel fluorinated benzodiazepine ligand, [¹⁸F]Fluoroethyltemazepam ([¹⁸F]F-FETEM), for positron emission tomography (PET) imaging of translocator protein (18 kDa). Methods: [¹⁸F]F-FETEM was radiolabelled with an automated synthesizer via a one-pot procedure. We conducted a [¹⁸F]F-aliphatic nucleophilic substitution of a tosylated precursor followed by purification on C18 and Alumina N SPE cartridges. Quality control tests was also carried out. Results: We obtained 2.0–3.0% decay-uncorrected radiochemical activity yield (3.7% decay-corrected) within the whole synthesis time about 33 min. The radiochemical purity of [¹⁸F]F-FETEM was over 90% by TLC analysis. Conclusions: This automated procedure may be used as basis for future production of [¹⁸F]F-FETEM for preclinical PET imaging studies. Full article

Positron emission tomography employing 6-l-[¹⁸F]fluoro-3,4-dihydroxyphenylalanine (6-l-[¹⁸F]FDOPA) is currently a highly relevant clinical tool for detection of gliomas, neuroendocrine tumors and evaluation of Parkinson’s disease progression. Yet, the deficiencies of electrophilic synthesis of 6-l-[¹⁸F]FDOPA hold back its wider use. To fulfill growing clinical demands for this radiotracer, novel synthetic strategies via direct nucleophilic ¹⁸F-radiloabeling starting from multi-Curie amounts of [¹⁸F]fluoride, have been recently introduced. In particular, Cu-mediated radiofluorination of arylpinacol boronates and arylstannanes show significant promise for introduction into clinical practice. In this short review these current developments will be discussed with a focus on their applicability to automation. Full article

Introduction: Benzotriazine-1,4-dioxides (BTDOs) such as tirapazamine (TPZ) and its derivatives act as radiosensitizers of hypoxic tissues. The benzotriazine-1-monoxide (BTMO) metabolite (SR 4317, TPZMO) of TPZ also has radiosensitizing properties, and via unknown mechanisms, is a potent enhancer of the radiosensitizing effects of TPZ. Unlike their 2-nitroimidazole radiosensitizer counterparts, radiolabeled benzotriazine oxides have not been used as radiopharmaceuticals for diagnostic imaging or molecular radiotherapy (MRT) of hypoxia. The radioiodination chemistry for preparing model radioiodinated BTDOs and BTMOs is now reported. Hypothesis: Radioiodinated 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (I-EOE-TPZ), a novel bioisosteric analogue of TPZ, and 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1-oxide (I-EOE-TPZMO), its monoxide analogue, are candidates for in vivo and in vitro investigations of biochemical mechanisms in pathologies that develop hypoxic microenvironments. In theory, both radiotracers can be prepared from the same precursors. Methods: Radioiodination procedures were based on classical nucleophilic [¹³¹I]iodide substitution on Tos-EOE-TPZ (P1) and by [¹³¹I]iodide exchange on I-EOE-TPZ (P2). Reaction parameters, including temperature, reaction time, solvent and the influence of pivalic acid on products’ formation and the corresponding radiochemical yields (RCY) were investigated. Results: The [¹³¹I]iodide labeling reactions invariably led to the synthesis of both products, but with careful manipulation of conditions the preferred product could be recovered as the major product. Radioiodide exchange on P2 in ACN at 80 ± 5 °C for 30 min afforded the highest RCY, 89%, of [¹³¹I]I-EOE-TPZ, which upon solid phase purification on an alumina cartridge gave 60% yield of the product with over 97% of radiochemical purity. Similarly, radioiodide exchange on P2 in ACN at 50 ± 5 °C for 30 min with pivalic acid afforded the highest yield, 92%, of [¹³¹I]I-EOE-TPZMO exclusively with no trace of [¹³¹I]I-EOE-TPZ. In both cases, extended reaction times and/or elevated temperatures resulted in the formation of at least two additional radioactive reaction products. Conclusions: Radioiodination of P1 and P2 with [¹³¹I]iodide leads to the facile formation of [¹³¹I]I-EOE-TPZMO. At 80 °C and short reaction times, the facile reduction of the N-4-oxide moiety was minimized to afford acceptable radiochemical yields of [¹³¹I]I-EOE-TPZ from either precursor. Regeneration of [¹³¹I]I-EOE-TPZ from [¹³¹I]I-EOE-TPZMO is impractical after reaction work-up. Full article

Phosphodiesterases (PDEs) are enzymes that play a major role in cell signalling by hydrolysing the secondary messengers cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) throughout the body and brain. Altered cyclic nucleotide-mediated signalling has been associated with a wide array of disorders, including neurodegenerative disorders. Recently, PDE5 has been shown to be involved in neurodegenerative disorders such as Alzheimer’s disease, but its precise role has not been elucidated yet. To visualize and quantify the expression of this enzyme in brain, we developed a radiotracer for specific PET imaging of PDE5. A quinoline-based lead compound has been structurally modified resulting in the fluoroethoxymethyl derivative ICF24027 with high inhibitory activity towards PDE5 (IC₅₀ = 1.86 nM). Radiolabelling with fluorine-18 was performed by a one-step nucleophilic substitution reaction using a tosylate precursor (RCY_(EOB) = 12.9% ± 1.8%; RCP > 99%; SA_(EOS) = 70–126 GBq/μmol). In vitro autoradiographic studies of [¹⁸F]ICF24027 on different mouse tissue as well as on porcine brain slices demonstrated a moderate specific binding to PDE5. In vivo studies in mice revealed that [¹⁸F]ICF24027 was metabolized under formation of brain penetrable radiometabolites making the radiotracer unsuitable for PET imaging of PDE5 in brain. Full article

With the idea of finding a more selective radiotracer for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression by means of positron emission tomography (PET), a novel [¹⁸F]fluorine radiolabeled pyrimidine with 4-hydroxy-3-(hydroxymethyl)butyl side chain at N-1 (HHB-5-[¹⁸F]FEP) was prepared and evaluated as a potential PET probe. Unlabeled reference compound, HHB-5-FEP, was synthesized via a five-step reaction sequence starting from 5-(2-acetoxyethyl)-4-methoxypyrimidin-2-one. The radiosynthesis of HHB-[¹⁸F]-FEP was accomplished by nucleophilic radiofluorination of a tosylate precursor using [¹⁸F]fluoride-cryptate complex in 45% ± 4 (n = 4) radiochemical yields and high purity (>99%). The biological evaluation indicated the feasibility of using HHB-5-[¹⁸F]FEP as a PET radiotracer for monitoring HSV1-tk expression in vivo. Full article

We previously reported ¹⁸F-labeled pyrazolo[1,5-a]pyrimidine derivatives: 7-(2-[¹⁸F]fluoroethylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile ([¹⁸F]1) and N-(2-(3-cyano-5-methylpyrazolo[1,5-a]pyrimidin-7-ylamino)ethyl)-2-[¹⁸F]fluoro-4-nitro- benzamide ([¹⁸F]2). Preliminary biodistribution experiments of both compounds showed s slow clearance rate from excretory tissues which warranted further investigation for tumor imaging with PET. Here we modified [¹⁸F]1 and [¹⁸F]2 by introducing polar groups such as ester, hydroxyl and carboxyl and developed three additional ¹⁸F-18 labeled pyrazolo[1,5-a] pyrimidine derivatives: (3-Cyano-7-(2-[¹⁸F]fluoroethylamino)pyrazolo[1,5-a]-pyrimidin-5- yl)methyl acetate ([¹⁸F]3), 7-(2-[¹⁸F]fluoroethylamino)-5-(hydroxymethyl)pyrazolo[1,5-a]- pyrimidine-3-carbonitrile ([¹⁸F]4) and (S)-6-(3-cyano-5-methylpyrazolo[1,5-a]pyrimidin-7-ylamino)-2-(2-[¹⁸F]fluoro-4-nitrobenzamido)hexanoic acid ([¹⁸F]5). The radiolabeled probes were synthesized by nucleophilic substitution of the corresponding tosylate and nitro precursors with ¹⁸F-fluoride. In Vitro studies showed higher uptake of [¹⁸F]3 and [¹⁸F]4 than that of [¹⁸F]5 by S180 tumor cells. In Vivo biodistribution studies in mice bearing S180 tumors showed that the uptake of both [¹⁸F]3 and [¹⁸F]4 in tumors displayed an increasing trend while the uptake of [¹⁸F]5 in tumor decreased through the course of the 120 min study. This significant difference in tumor uptake was also found between [¹⁸F]1 and [¹⁸F]2. Thus, we compared the biological behavior of the five tracers and reported the tumor uptake kinetic differences between 2-[¹⁸F]fluoroethylamino- and 2-[¹⁸F]fluoro-4-nitro- benzamidopyrazolo[1,5-a] pyrimidine derivatives. Full article