Journal of labelled compounds & radiopharmaceuticals最新文献

Trans-blood–brain barrier (BBB) delivery of therapeutic and diagnostic agents is a major challenge in the development of central nervous system (CNS) targeted radiopharmaceuticals. This review is an introduction to the use of peptides as delivery agents to transport cargos into the CNS. The most widely used BBB-penetrating peptides are reviewed here, with a particular emphasis on the broad range of cargos delivered into the CNS using these. Cell-penetrating peptides (CPPs) have been deployed as trans-BBB delivery agents for some time; new developments in the CPP field offer exciting opportunities for the design of next generation trans-BBB complexes. Many of the peptides highlighted here are ready to be combined with diagnostic and therapeutic radiopharmaceuticals to develop highly effective CNS-targeted agents.

The generation of amyloid beta peptides that aggregate in the brain is believed to play a major role in Alzheimer's disease. In theory, the inhibition of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), which catalyzes the initial rate-limiting step in amyloid beta production, may slow or stop Alzheimer's disease. Herein, we report the preparation of two potent BACE1 inhibitors, BI 1147560 (1) and BI 1181181 (2), labeled with carbon-14 and with deuterium. The use of advanced key chiral intermediates like 3 and 5 shortened the carbon-14 syntheses of these two compounds to five and six steps, respectively, and helped in preparing them with very high chemical purity and enantiomeric excess without deviating from the process chemistry route. For the deuterium synthesis, oxetan-3-ylmethanamine [²H₆]-7 and 2-fluoro-2-methylpropan-1-amine [²H₆]-9 were prepared then used with the chiral intermediate 5 to furnish deuterium labeled 1 and 2, respectively.

Positron emission tomography (PET) is a powerful tool for imaging biological processes in the central nervous system (CNS). Designing PET radiotracers capable of crossing the blood–brain barrier (BBB) remains a major challenge. In addition to being brain-penetrant, a quantifiable CNS PET radiotracer must have high target affinity and selectivity, appropriate pharmacokinetics, minimal non-specific binding, negligible radiometabolites in the brain, and generally must be amenable to labeling with carbon-11 (¹¹C) or fluorine-18 (¹⁸F). This review aims to give an overview of some of the critical physicochemical and biochemical contributors specific for CNS PET radiotracer design and how they can differ from pharmaceutical drug development, including in vitro assays, in silico predictions, and in vivo studies, with examples for how such methods can be implemented to optimize brain uptake of radiotracers based on experiences from our neuroimaging program.

α-deuterated carboxylic acids have been synthesized from the corresponding malonic acids via hydrogen/deuterium exchange and decarboxylation in presence of D₂O. The method is general, mild and efficient and does not require organic solvents or other additives. Yields range between 83% and 94% and purification was not necessary. Starting materials were easy accessible and the α-deuterated carboxylic acids may easily be transformed to other labeled compounds such as alcohols, aldehydes, esters, and amides. Characterization with NMR confirmed purity and isotopic purity.

Organotrifluoroborates have gained acceptance as radioprosthetic groups for radiofluorination. Of these, the zwitterionic prosthetic group “AMBF₃” with a quaternary dimethylammonium ion dominates the trifluoroborate space. Herein, we report on imidazolium-methylene trifluoroborate (ImMBF₃) as an alternative radioprosthetic group and report on its properties in the context of a PSMA-targeting EUK ligand that was previously been conjugated to AMBF₃. The ImMBF₃ is readily synthesized from imidazole and conjugated via CuAAC “click” chemistry to give a structure similar to PSMA-617. ¹⁸F-labeling proceeded in one step per our previous reports and imaged in LNCaP-xenograft bearing mice. The [¹⁸F]-PSMA-617-ImMBF₃ tracer proved to be less polar (LogP_7.4 = −2.95 ± 0.03) while showing a significantly lower solvolytic rate (t_1/2 = 8100 min) and slightly higher molar activity (Am) at 174 ± 38 GBq/μmol. Tumor uptake was measured at 13.7 ± 4.8%ID/g and a tumor:muscle ratio of 74.2 ± 35.0, tumor:blood ratio of 21.4 ± 7.0, tumor:kidney ratio of 0.29 ± 0.14, and tumor:bone ratio of 23.5 ± 9.5. In comparison with previously reported PSMA-targeting EUK-AMBF₃ conjugates, we have altered the LogP_7.4 value, tuned the solvolytic half-life of the prosthetic, and increased radiochemical conversion while achieving similar tumor uptake, contrast ratios, and molar activities compared with AMBF₃ bioconjugates.

[¹⁸F]FTC-146 was introduced as a very potent and selective sigma-1 receptor radioligand, which has shown promising application as an imaging agent for neuropathic pain with positron emission tomography. In line with a multi-laboratory project on animal welfare, we chose this radioligand to investigate its potential for detecting neuropathic pain and tissue damage in tumor-bearing animals. However, the radiochemical yield (RCY) of around 4–7% was not satisfactory to us, and efforts were made to improve it. Herein, we describe an improved approach for the radiosynthesis of [¹⁸F]FTC-146 resulting in a RCY, which is sevenfold higher than that previously reported. A tosylate precursor was synthesized and radio-fluorination experiments were performed via aliphatic nucleophilic substitution reactions using either K[¹⁸F]F-Kryptofix®222 (K_2.2.2)-carbonate system or tetra-n-butylammonium [¹⁸F]fluoride ([¹⁸F]TBAF). Several parameters affecting the radiolabeling reaction such as solvent, ¹⁸F-fluorination agent with the corresponding amount of base, labeling time, and temperature were investigated. Best labeling reaction conditions were found to be [¹⁸F]TBAF and acetonitrile as solvent at 100°C. The new protocol was then translated to an automated procedure using a FX2 N synthesis module. Finally, the radiotracer reproducibly obtained with RCYs of 41.7 ± 4.4% in high radiochemical purity (>98%) and molar activities up to 171 GBq/μmol.

We report the synthesis and biological evaluation of ¹³¹I-labeled antihuman tumor-derived immunoglobulin G (IgG) light chain monoclonal antibody (4E9) ([¹³¹I]I-4E9) as a promising probe for tumor imaging. [¹³¹I]I-4E9 was synthesized in radiochemical yield of 89.9 ± 4.7% with radiochemical purity of more than 99%. [¹³¹I]I-4E9 showed high stability in normal saline and human serum. In cell uptake studies, [¹³¹I]I-4E9 exhibited favorable binding affinity and high specificity in HeLa MR cells. In biodistribution studies, [¹³¹I]I-4E9 showed high tumor uptake, high tumor/non-tumor ratios, and specific binding in BALB/c nu/nu mice bearing human HeLa MR xenografts. Single-photon emission computerized tomography (SPECT) imaging of [¹³¹I]I-4E9 in the HeLa MR xenograft model demonstrated clear visualization of tumor after 48 h and confirmed specific binding in tumor. These findings suggest that [¹³¹I]I-4E9 possesses favorable biological characteristics and warrants further investigation as a prospective probe for imaging and treatment of cancers.

CuI-mediated ¹¹C-cyanation was evaluated by synthesizing [¹¹C]perampanel ([¹¹C]5) as a model compound and compared with previous reports. To a DMF solution with 5′-(2-bromophenyl)-1′-phenyl-[2,3′-bipyridin]-6′(1′H)-one (4) and CuI, [¹¹C]NH₄CN in a stream of ammonia/nitrogen (5:95, v/v) gas was bubbled. Subsequently, the reaction mixture was heated at 180°C for 5 min. After HPLC purification, [¹¹C]5 was obtained in 7.2 ± 1.0% (n = 4) non-decay corrected radiochemical yield with >99% radiochemical purity and a molar activity of 98 ± 28 GBq/μmol. In vivo evaluations of [¹¹C]5 were performed using small animals. PET scans to check the kinetics of [¹¹C]5 in the whole body of mice suggested that [¹¹C]5 spreads rapidly into the brain, heart, and lungs and then accumulates in the small intestine. To evaluate the performance of CuI-mediated ¹¹C-cyanation reaction, bromobenzene (6a) was selected as the model compound; however, it failed. Therefore, optimization of the reaction conditions has been performed, and consequently, the addition of K₂CO₃ and prolonging the reaction time improved the radiochemical yield about double. With this improved method, CuI-mediated ¹¹C-cyanation of various (hetero)aromatic bromides was performed to exhibit the tolerance of most functional groups and to provide ¹¹C-cyanated products in good to moderate radiochemical yields.

Selective deuterium installation into small molecules is becoming increasingly desirable not only for the elucidation of mechanistic pathways and studying biological processes but also because of deuterium's ability to favorably adjust the pharmacokinetic parameters of bioactive molecules. Fused bicyclic moieties, especially those containing heteroatoms, are prevalent in drug discovery and pharmaceuticals. Herein, we report a copper-catalyzed transfer hydrodeuteration of cyclic and heterocyclic alkenes, which enables the synthesis of chromans, quinolinones, and tetrahydronaphthalenes that are precisely deuterated at the benzylic position. We also demonstrate the ability to place one deuterium atom at the homobenzylic site of these scaffolds with high regioselectivity by swapping transfer reagents for their isotopic analogs. Furthermore, examples of chemoselective transfer hydrogenation and transfer deuteration are disclosed, allowing for the simultaneous incorporation of two vicinal hydrogen or deuterium atoms into a double bond.

Angiotensin II type 1 receptors (AT₁R) blocker losartan is used in patients with renal and cardiovascular diseases. [¹⁸F]fluoropyridine-losartan has shown favorable binding profile for quantitative renal PET imaging of AT₁R with selective binding in rats and pigs, low interference of radiometabolites and appropriate dosimetry for clinical translation. A new approach was developed to produce [¹⁸F]fluoropyridine-losartan in very high molar activity. Automated radiosynthesis was performed in a three-step, two-pot, and two-HPLC-purification procedure within 2 h. Pure [¹⁸F]FPyKYNE was obtained by radiofluorination of NO₂PyKYNE and silica-gel-HPLC purification (40 ± 9%), preventing the formation of nitropyridine-losartan in the second step. Conjugation with trityl-losartan azide via click chemistry, followed by acid hydrolysis, C18-HPLC purification and reformulation provided [¹⁸F]fluoropyridine-losartan in 11 ± 2% (decay-corrected from [¹⁸F]fluoride, EOB). Using tris[(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methyl]-amine (THPTA) as a Cu(I)-stabilizing agent for coupling [¹⁸F]FPyKYNE to the unprotected losartan azide afforded [¹⁸F]fluoropyridine-losartan in similar yields (11 ± 3%, decay-corrected from [¹⁸F]fluoride, EOB). Reverse-phase HPLC was optimized by reducing the pH of the mobile phase to achieve complete purification and high molar activities (467 ± 60 GBq/μmol). The use of radioprotectants prevented tracer radiolysis for 10 h (RCP > 99%). The product passed the quality control testing. This reproducible automated radiosynthesis process will allow in vivo PET imaging of AT₁R expression in several diseases.