Alkylative Aziridine Ring-Opening Reactions

In this study, the highly strained three-membered aziridine ring was successfully activated as the aziridinium ion by alkylation of the ring nitrogen with a methyl, ethyl or allyl group, which was followed by ring opening with external nucleophiles such as acetate and azide. Such alkylative aziridine ring opening provides an easy route for the synthesis of various N-alkylated amine-containing molecules with concomitant introduction of an external nucleophile at either its α- or β-position.     

Regioselective ring opening of 2-methylaziridine derivatives with F- and F-fluoride

Regioselectivity of the nucleophilic ring opening of N-benzoyl (Bz) and N-benzyloxycarbonyl (Cbz) activated 2-methylaziridines with anhydrous tetramethylammonium fluoride, anhydrous hydrogen fluoride, and ¹⁹F or [¹⁸F]-labelled potassium cryptand fluoride ([K₂₂₂][^18/19F]) were investigated. Whereas all reactions with rigorously anhydrous N(CH₃)₄F did not ring-open the aziridines, reactions with anhydrous HF exclusively yielded the 2-fluoropropanamine derivatives. Reactions of Bz-protected and Cbz-protected 2-methylaziridine with [K₂₂₂][^18/19F] yielded the 2-fluoropropanamine and 1-fluoro-2-propanamine derivatives as the major products, respectively, and represents the first example of regiocontrol during ring opening of aziridines with [¹⁸F]-fluoride.     

Synthesis of [18F]F-γ-T-3, a Redox-Silent γ-Tocotrienol (γ-T-3) Vitamin E Analogue for Image-Based In Vivo Studies of Vitamin E Biodistribution and Dynamics

Vitamin E, a natural antioxidant, is of interest to scientists, health care pundits and faddists; its nutritional and biomedical attributes may be validated, anecdotal or fantasy. Vitamin E is a mixture of tocopherols (TPs) and tocotrienols (T-3s), each class having four substitutional isomers (α-, β-, γ-, δ-). Vitamin E analogues attain only low concentrations in most tissues, necessitating exacting invasive techniques for analytical research. Quantitative positron emission tomography (PET) with an F-18-labeled molecular probe would expedite access to Vitamin E’s biodistributions and pharmacokinetics via non-invasive temporal imaging. (R)-6-(3-[¹⁸F]Fluoropropoxy)-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-chromane ([¹⁸F]F-γ-T-3) was prepared for this purpose. [¹⁸F]F-γ-T-3 was synthesized from γ-T-3 in two steps: (i) 1,3-di-O-tosylpropane was introduced at C6-O to form TsO-γ-T-3, and (ii) reaction of this tosylate with [¹⁸F]fluoride in DMF/K₂₂₂. Non-radioactive F-γ-T-3 was synthesized by reaction of γ-T-3 with 3-fluoropropyl methanesulfonate. [¹⁸F]F-γ-T-3 biodistribution in a murine tumor model was imaged using a small-animal PET scanner. F-γ-T-3 was prepared in 61% chemical yield. [¹⁸F]F-γ-T-3 was synthesized in acceptable radiochemical yield (RCY 12%) with high radiochemical purity (>99% RCP) in 45 min. Preliminary F-18 PET images in mice showed upper abdominal accumulation with evidence of renal clearance, only low concentrations in the thorax (lung/heart) and head, and rapid clearance from blood. [¹⁸F]F-γ-T-3 shows promise as an F-18 PET tracer for detailed in vivo studies of Vitamin E. The labeling procedure provides acceptable RCY, high RCP and pertinence to all eight Vitamin E analogues.     

Clinical Relevance of [18F]Florbetaben and [18F]FDG PET/CT Imaging on the Management of Patients with Dementia

PET of β-Amyloid plaques (Aβ) using [¹⁸F]florbetaben ([¹⁸F]FBB) and [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) increasingly aid clinicians in early diagnosis of dementia, including Alzheimer’s disease (AD), frontotemporal disease, dementia with Lewy bodies, and vascular dementia. The aim of this retrospective analysis was to evaluate clinical relevance of [¹⁸F]FBB, [¹⁸F]FDG PET and complimentary CSF measurements in patients with suspected dementia. In this study, 40 patients with clinically suspected or history of dementia underwent (1) measurement of Aβ peptides, total tau, and p-tau protein levels in the cerebrospinal fluid (CSF) compared with healthy controls (HC); (2) clinical and neuropsychological assessment, which included Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological assessment battery (CERAD-NAB); (3) [¹⁸F]FBB and [¹⁸F]FDG PET imaging within an average of 3 weeks. The subjects were within 15 days stratified using PET, CSF measurements as HC, mild cognitive impaired (MCI) and dementia including Alzheimer´s disease. The predictive dementia-related cognitive decline values were supporting the measurements. PET images were evaluated visually and quantitatively using standard uptake value ratios (SUVR). Twenty-one (52.5%) subjects were amyloid-positive (Aβ+), with a median neocortical SUVR of 1.80 for AD versus 1.20 relative to the respective 19 (47.5 %) amyloid-negative (Aβ-) subjects. Moreover, the [¹⁸F]FDG and [¹⁸F]FBB confirmed within a sub-group of 10 patients a good complimentary role by correlation between amyloid pathology and brain glucose metabolism in 8 out of 10 subjects. The results suggest the clinical relevance for [¹⁸F]FBB combined with [¹⁸F]FDG PET retention and CFS measurements serving the management of our patients with dementia. Therefore, [¹⁸F]FBB combined with [¹⁸F]FDG PET is a helpful tool for differential diagnosis, and supports the patients’ management as well as treatment.     

[18F]Nifene PET/CT Imaging in Mice: Improved Methods and Preliminary Studies of α4β2* Nicotinic Acetylcholinergic Receptors in Transgenic A53T Mouse Model of α-Synucleinopathy and Post-Mortem Human Parkinson’s Disease

We report [¹⁸F]nifene binding to α4β2* nicotinic acetylcholinergic receptors (nAChRs) in Parkinson’s disease (PD). The study used transgenic Hualpha-Syn(A53T) PD mouse model of α-synucleinopathy for PET/CT studies in vivo and autoradiography in vitro. Additionally, postmortem human PD brain sections comprising of anterior cingulate were used in vitro to assess translation to human studies. Because the small size of mice brain poses challenges for PET imaging, improved methods for radiosynthesis of [¹⁸F]nifene and simplified PET/CT procedures in mice were developed by comparing intravenous (IV) and intraperitoneal (IP) administered [¹⁸F]nifene. An optimal PET/CT imaging time of 30–60 min post injection of [¹⁸F]nifene was established to provide thalamus to cerebellum ratio of 2.5 (with IV) and 2 (with IP). Transgenic Hualpha-Syn(A53T) mice brain slices exhibited 20–35% decrease while in vivo a 20–30% decrease of [¹⁸F]nifene was observed. Lewy bodies and α-synuclein aggregates were confirmed in human PD brain sections which lowered the [¹⁸F]nifene binding by more than 50% in anterior cingulate. Thus [¹⁸F]nifene offers a valuable tool for PET imaging studies of PD.     

Alpha selective epoxide opening with F: synthesis of 4-(3-[F]fluoro-2-hydroxypropoxy)benzaldehyde ([F]FPB) for peptide labeling

Strained tricyclic ring systems such as epoxides are rarely used as precursors for the introduction of anionic fluorine-18 into organic compounds intended for positron emission tomography (PET). Here we report the alpha selective ring opening of epoxides for the introduction of fluorine-18 into small as well as larger biomolecules via 1- and 2-step protocols. [¹⁸F]fluoromisonidazole ([¹⁸F]MISO), a tracer for hypoxia imaging, and the tumor targeting peptide Tyr³-octreotate (TATE) were radiolabeled using epoxide opening reactions. In the latter case, the new prosthetic labeling synthon 4-(3-[¹⁸F]fluoro-2-hydroxypropoxy)benzaldehyde ([¹⁸F]FPB) has been used for ¹⁸F-introduction.     

An Improved Synthesis of N-(4-[18F]Fluorobenzoyl)-Interleukin-2 for the Preclinical PET Imaging of Tumour-Infiltrating T-cells in CT26 and MC38 Colon Cancer Models

Positron emission tomography (PET) imaging of activated T-cells with N-(4-[¹⁸F]fluorobenzoyl)-interleukin-2 ([¹⁸F]FB-IL-2) may be a promising tool for patient management to aid in the assessment of clinical responses to immune therapeutics. Unfortunately, existing radiosynthetic methods are very low yielding due to complex and time-consuming chemical processes. Herein, we report an improved method for the synthesis of [¹⁸F]FB-IL-2, which reduces synthesis time and improves radiochemical yield. With this optimized approach, [¹⁸F]FB-IL-2 was prepared with a non-decay-corrected radiochemical yield of 3.8 ± 0.7% from [¹⁸F]fluoride, 3.8 times higher than previously reported methods. In vitro experiments showed that the radiotracer was stable with good radiochemical purity (>95%), confirmed its identity and showed preferential binding to activated mouse peripheral blood mononuclear cells. Dynamic PET imaging and ex vivo biodistribution studies in naïve Balb/c mice showed organ distribution and kinetics comparable to earlier published data on [¹⁸F]FB-IL-2. Significant improvements in the radiochemical manufacture of [¹⁸F]FB-IL-2 facilitates access to this promising PET imaging radiopharmaceutical, which may, in turn, provide useful insights into different tumour phenotypes and a greater understanding of the cellular nature and differential immune microenvironments that are critical to understand and develop new treatments for cancers.     

Pd-η 3-C6H9 complexes of the Trost modular ligand: high nuclearity columnar aggregation controlled by concentration,solvent and counterion

Under optimised conditions, the Trost modular ligand (TML) series induces high levels of asymmetric induction in an extraordinarily wide range of reactions involving palladium π-allyl intermediates. Prior mechanistic investigations into reactions involving Pd-η ³-C₆H₉ intermediates have focussed on the monomeric 13-membered ring formed via P,P-chelation of the ligand to Pd. However, it is also recognised that ring-opening oligomerisation provides a pool of high nuclearity Pd-η ³-C₆H₉ species that, by affording a low level, or even the opposite sense, of asymmetric induction relative to the mononuclear species, are responsible for a reduction in selectivity under non-optimised conditions. Herein we describe an investigation by NMR spectroscopy, molecular mechanics, molecular dynamics, and small-angle neutron scattering (SANS), of a Pd-η ³-C₆H₉ cation bearing the 1,2-diaminocyclohexane TML ligand (2). Using both nondeuterated and perdeuterated (D₄₇) isotopologues of the resulting complexes ([1]⁺), we show that a two-stage oligomerisation-aggregation process forms self assembled cylindrical aggregates of very high nuclearity (up to 56 Pd centres). We also investigate how concentration, solvent and counter-anion all modulate the extent of oligomerisation.     

Reactions of 1-alkoxycarbonylaziridines with nucleophilic reagents

1-Methoxycarbonylaziridines react under mild conditions with a number of nucleophilic reagents such as water, acids, alcohols, and amines with opening of the aziridine ring. In the case of 7-methoxycarbonyl-7-azabicyclo[4.1.0]heptane it was shown by PMR spectroscopy that the ring-opening reaction is realized stereoselectively to give trans-1,2-disubstituted cyclohexanes.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1054–1057, August, 1981.     

[89Zr]-Pertuzumab PET Imaging Reveals Paclitaxel Treatment Efficacy Is Positively Correlated with HER2 Expression in Human Breast Cancer Xenograft Mouse Models

Paclitaxel (PTX) treatment efficacy varies in breast cancer, yet the underlying mechanism for variable response remains unclear. This study evaluates whether human epidermal growth factor receptor 2 (HER2) expression level utilizing advanced molecular positron emission tomography (PET) imaging is correlated with PTX treatment efficacy in preclinical mouse models of HER2+ breast cancer. HER2 positive (BT474, MDA-MB-361), or HER2 negative (MDA-MB-231) breast cancer cells were subcutaneously injected into athymic nude mice and PTX (15 mg/kg) was administrated. In vivo HER2 expression was quantified through [⁸⁹Zr]-pertuzumab PET/CT imaging. PTX treatment response was quantified by [¹⁸F]-fluorodeoxyglucose ([¹⁸F]-FDG) PET/CT imaging. Spearman’s correlation, Kendall’s tau, Kolmogorov–Smirnov test, and ANOVA were used for statistical analysis. [⁸⁹Zr]-pertuzumab mean standard uptake values (SUV_mean) of BT474 tumors were 4.9 ± 1.5, MDA-MB-361 tumors were 1.4 ± 0.2, and MDA-MB-231 (HER2−) tumors were 1.1 ± 0.4. [¹⁸F]-FDG SUV_mean changes were negatively correlated with [⁸⁹Zr]-pertuzumab SUV_mean (r = −0.5887, p = 0.0030). The baseline [¹⁸F]-FDG SUV_mean was negatively correlated with initial [⁸⁹Zr]-pertuzumab SUV_mean (r = −0.6852, p = 0.0002). This study shows PTX treatment efficacy is positively correlated with HER2 expression level in human breast cancer mouse models. Molecular imaging provides a non-invasive approach to quantify biological interactions, which will help in identifying chemotherapy responders and potentially enhance clinical decision-making.     

[124I]IBETA: A New Aβ Plaque Positron Emission Tomography Imaging Agent for Alzheimer’s Disease

Several fluorine-18-labeled PET β-amyloid (Aβ) plaque radiotracers for Alzheimer’s disease (AD) are in clinical use. However, no radioiodinated imaging agent for Aβ plaques has been successfully moved forward for either single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Radioiodinated pyridyl benzofuran derivatives for the SPECT imaging of Aβ plaques using iodine-123 and iodine-125 are being pursued. In this study, we assess the iodine-124 radioiodinated pyridyl benzofuran derivative 5-(5-[¹²⁴I]iodobenzofuran-2-yl)-N,N-dimethylpyridin-2-amine ([¹²⁴I]IBETA) (Ki = 2.36 nM) for utilization in PET imaging for Aβ plaques. We report our findings on the radioiododestannylation reaction used to prepare [^124/125I]IBETA and evaluate its binding to Aβ plaques in a 5 × FAD mouse model and postmortem human AD brain. Both [¹²⁵I]IBETA and [¹²⁴I]IBETA are produced in >25% radiochemical yield and >85% radiochemical purity. The in vitro binding of [¹²⁵I]IBETA and [¹²⁴I]IBETA in transgenic 5 × FAD mouse model for Aβ plaques was high in the frontal cortex, anterior cingulate, thalamus, and hippocampus, which are regions of high Aβ accumulation, with very little binding in the cerebellum (ratio of brain regions to cerebellum was >5). The in vitro binding of [¹²⁵I]IBETA and [¹²⁴I]IBETA in postmortem human AD brains was higher in gray matter containing Aβ plaques compared to white matter (ratio of gray to white matter was >5). Anti-Aβ immunostaining strongly correlated with [¹²⁴/¹²⁵I]IBETA regional binding in both the 5 × FAD mouse and postmortem AD human brains. The binding of [¹²⁴/¹²⁵I]IBETA in 5 × FAD mouse and postmortem human AD brains was displaced by the known Aβ plaque imaging agent, Flotaza. Preliminary PET/CT studies of [¹²⁴I]IBETA in the 5 × FAD mouse model suggested [¹²⁴I]IBETA was relatively stable in vivo with a greater localization of [¹²⁴I]IBETA in the brain regions with a high concentration of Aβ plaques. Some deiodination was observed at later time points. Therefore, [¹²⁴I]IBETA may potentially be a useful PET radioligand for Aβ plaques in brain studies.     

Involvement of the γ Isoform of cPLA2 in the Biosynthesis of Bioactive N-Acylethanolamines

Arachidonylethanolamide (anandamide) acts as an endogenous ligand of cannabinoid receptors, while other N-acylethanolamines (NAEs), such as palmitylethanolamide and oleylethanolamide, show analgesic, anti-inflammatory, and appetite-suppressing effects through other receptors. In mammalian tissues, NAEs, including anandamide, are produced from glycerophospholipid via N-acyl-phosphatidylethanolamine (NAPE). The ɛ isoform of cytosolic phospholipase A₂ (cPLA₂) functions as an N-acyltransferase to form NAPE. Since the cPLA₂ family consists of six isoforms (α, β, γ, δ, ɛ, and ζ), the present study investigated a possible involvement of isoforms other than ɛ in the NAE biosynthesis. Firstly, when the cells overexpressing one of the cPLA₂ isoforms were labeled with [¹⁴C]ethanolamine, the increase in the production of [¹⁴C]NAPE was observed only with the ɛ-expressing cells. Secondly, when the cells co-expressing ɛ and one of the other isoforms were analyzed, the increase in [¹⁴C]N-acyl-lysophosphatidylethanolamine (lysoNAPE) and [¹⁴C]NAE was seen with the combination of ɛ and γ isoforms. Furthermore, the purified cPLA₂γ hydrolyzed not only NAPE to lysoNAPE, but also lysoNAPE to glycerophospho-N-acylethanolamine (GP-NAE). Thus, the produced GP-NAE was further hydrolyzed to NAE by glycerophosphodiesterase 1. These results suggested that cPLA₂γ is involved in the biosynthesis of NAE by its phospholipase A₁/A₂ and lysophospholipase activities.     

The Identification of New Triterpenoids in Eucalyptus globulus Wood

Eight polyhydroxy triterpenoid acids, hederagenin, (4α)-23-hydroxybetulinic acid, maslinic acid, corosolic acid, arjunolic acid, asiatic acid, caulophyllogenin, and madecassic acid, with 2, 3, and 4 hydroxyl substituents, were identified and quantified in the dichloromethane extract of Eucalyptus globulus wood by comparing their GC-retention time and mass spectra with standards. Two other triterpenoid acids were tentatively identified by analyzing their mass spectra, as (2α)-2-hydroxybetulinic acid and (2α,4α)-2,23-dihydroxybetulinic acid, with 2 and 3 hydroxyl substituents. Two MS detectors were used, a quadrupole ion trap (QIT) and a quadrupole mass filter (QMF). The EI fragmentation pattern of the trimethylsilylated polyhydroxy structures of these triterpenoid acids is characterized by the sequential loss of the trimethylsilylated hydroxyl groups, most of them by the retro-Diels-Alder (rDA) opening of the C ring with a π-bond at C12-C13. The rDA C-ring opening produces ions at m/z 320 (or 318) and m/z 278 (or 277, 276, 366). Sequential losses of the hydroxyl groups produce ions with m/z from [M - 90] to [M - 90*y], where y is the number of hydroxyl substituents present (from 2 to 4). Moreover, specific cleavage in ring E was observed, passing from m/z 203 to m/z 133 and conducting other major fragments such as m/z 189.     

Challenges in the Highly Selective [3 + 1]-Cycloaddition of an Enoldiazoacetamide to Form a Donor–Acceptor Cis-Cyclobutenecarboxamide

A substituted donor–acceptor cyclobutenecarboxamide is synthesized with modest enantiocontrol through a chiral copper(I) complex catalyzed [3 + 1]-cycloaddition reaction of α-acyl diphenylsulfur ylides with 3-siloxy-2-diazo-3-butenamides. With a methyl substituent on the 4-position of the 3-butenamide, the cis-vicinal-3,4-disubstituted cyclobutenecarboxamide is formed with >20:1 diastereocontrol. Donor-acceptor 3-methyl-2-siloxycyclopropenecarboxamide is rapidly formed from the reactant enoldiazoamide and undergoes catalytic ring opening to give only the Z-γ-substituted metallo-enolcarbene. Elimination from 3-siloxy-2-diazo-3-pentenamide to form the conjugated 3-siloxy-2,4-pentadienamide is competitive but minimized at low temperature.     

[F]Fluoromethyl iodide ([F]FCH2I): preparation and reactions with phenol, thiophenol, amide and amine functional groups

In this study, we report the synthesis and reactivity of [¹⁸F]fluoromethyl iodide ([¹⁸F]FCH₂I) with various nucleophilic substrates and the stabilities of [¹⁸F]fluoromethylated compounds. [¹⁸F]FCH₂I was prepared by reacting diiodomethane (CH₂I₂) with [¹⁸F]KF, and purified by distillation in radiochemical yields of 14-31% (n = 25). [¹⁸F]FCH₂I was stable in organic solvents commonly used for labeling and aqueous solution with pH 1-7, but was unstable in basic solutions. [¹⁸F]FCH₂I displayed a high reactivity with various nucleophilic substrates such as phenol, thiophenol, amide and amine. The [¹⁸F]fluoromethylated compounds synthesized by the reactions of phenol, thiophenol and tertiary amine with [¹⁸F]FCH₂I were stable for purification, formulation and storage. In contrast, the [¹⁸F]fluoromethylated compounds synthesized by the reactions of primary or secondary amines, and amide with [¹⁸F]FCH₂I were too unstable to be detected or purified from the reaction mixtures. Defluorination of these [¹⁸F]fluoromethyl compounds was a main decomposition route.     

Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-O-(2-Fluoroethyl) Moiety and the Potential of Their 18F-Labeled Derivatives for Neuroinflammation Imaging

Neolignans honokiol and 4′-O-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in vivo. Recent studies of [¹¹C]MPbP (4′-[¹¹C]methoxy-5-propyl-1,1′-biphenyl-2-ol) biodistribution in LPS (lipopolysaccharide)-treated rats have confirmed the high potential of MH derivatives for imaging neuroinflammation. Here, we report the synthesis of four structural analogs of honokiol, of which 4′-(2-fluoroethoxy)-2-hydroxy-5-propyl-1, 1′-biphenyl (F-IV) was selected for labeling with fluorine-18 (T_1/2 = 109.8 min) due to its high anti-inflammatory activity confirmed by enzyme immunoassays (EIA) and neuromorphological studies. The high inhibitory potency of F-IV to COX-2 and its moderate lipophilicity and chemical stability are favorable factors for the preliminary evaluation of the radioligand [¹⁸F]F-IV in a rodent model of neuroinflammation. [¹⁸F]F-IV was prepared with good radiochemical yield and high molar activity and radiochemical purity by ¹⁸F-fluoroethylation of the precursor with Boc-protecting group (15) with [¹⁸F]2-fluoro-1-bromoethane ([¹⁸F]FEB). Ex vivo biodistribution studies revealed a small to moderate increase in radioligand uptake in the brain and peripheral organs of LPS-induced rats compared to control animals. Pretreatment with celecoxib resulted in significant blocking of radioactivity uptake in the brain (pons and medulla), heart, lungs, and kidneys, indicating that [¹⁸F]F-IV is likely to specifically bind to COX-2 in a rat model of neuroinflammation. However, in comparison with [¹¹C]MPbP, the new radioligand showed decreased brain uptake in LPS rats and high retention in the blood pool, which apparently could be explained by its high plasma protein binding. We believe that the structure of [¹⁸F]F-IV can be optimized by replacing the substituents in the biphenyl core to eliminate these disadvantages and develop new radioligands for imaging activated microglia.     

[F]Fluoroamines via ring-opening of N-Cbz-2-methylaziridine with [F]-fluoride

A highly regioselective method was developed for ring-opening benzyloxycarbonyl (Cbz)-protected 2-methylaziridine with [¹⁸F]-labelled fluoride. Following catalytic hydrogenation, 1-[¹⁸F]fluoro-2-propanamine ([¹⁸F]1) and 2-[¹⁸F]fluoro-1-propanamine ([¹⁸F]2) were prepared as the major and minor products, respectively (85:15), and were characterized following acylation with benzyl chloride. This methodology is applicable towards the generation of new [¹⁸F]-labelled amines for incorporation into radiopharmaceuticals.     

Cyclodextrins Initiated Ring-Opening Polymerization of Lactide Using 4-Dimethylaminopyridine (DMAP) as Catalyst: Study of DMAP/β-CD Inclusion Complex and Access to New Structures

Cyclodextrins (CDs) are cyclic oligosaccharides used in many fields. Grafting polymers onto CDs enables new structures and applications to be obtained. Polylactide (PLA) is a biobased, biocompatible aliphatic polyester that can be grafted onto CDs by -OH-initiated ring-opening polymerization. Using 4-dimethylaminopyridine (DMAP) as an organocatalyst, a quantitative functionalization is reached on native α-, β-, γ- and 2,3-dimethyl- β-cyclodextrins. Narrow molecular weight distributions are obtained with the native CDs (dispersity < 1.1). The DMAP/β-CD combination is used as a case study, and the formation of an inclusion complex (1/1) is shown for the first time in the literature, which is fully characterized by NMR. The inclusion of DMAP into the cavity occurs via the secondary rim of the β-CD and the association constant (K_a) is estimated to be 88.2 M⁻¹. Its use as an initiator for ring-opening polymerization leads to a partial functionalization efficiency, and thus a more hydrophilic β-CD-PLA conjugate than that obtained starting from native β-CD. Polymerization results including also the use of the adamantane/β-CD inclusion complex as an initiator suggest that inclusion of the DMAP catalyst into the CD may not occur during polymerization reactions. Rac-lactide does not form an inclusion complex with β-CD.     

A Comprehensive Investigation of the Structural,Thermal, and Biological Properties of Fully Randomized Biomedical Polyesters Synthesized with a Nontoxic Bismuth(III) Catalyst

Aliphatic polyesters are the most common type of biodegradable synthetic polymer used in many pharmaceutical applications nowadays. This report describes the ring-opening polymerization (ROP) of l-lactide (L-LA), ε-caprolactone (CL) and glycolide (Gly) in the presence of a simple, inexpensive and convenient PEG200-BiOct₃ catalytic system. The chemical structures of the obtained copolymers were characterized by ¹H- or ¹³C-NMR. GPC was used to estimate the average molecular weight of the resulting polyesters, whereas TGA and DSC were employed to determine the thermal properties of polymeric products. The effects of temperature, reaction time, and catalyst content on the polymerization process were investigated. Importantly, the obtained polyesters were not cyto- or genotoxic, which is significant in terms of the potential for medical applications (e.g., for drug delivery systems). As a result of transesterification, the copolymers obtained had a random distribution of comonomer units along the polymer chain. The thermal analysis indicated an amorphous nature of poly(l-lactide-co-ε-caprolactone) (PLACL) and a low degree of crystallinity of poly(ε-caprolactone-co-glycolide) (PCLGA, X_c = 15.1%), in accordance with the microstructures with random distributions and short sequences of comonomer units (l = 1.02–2.82). Significant differences in reactivity were observed among comonomers, confirming preferential ring opening of L-LA during the copolymerization process.     

Development of Radiogallium-Labeled Peptides for Platelet-Derived Growth Factor Receptor β (PDGFRβ) Imaging: Influence of Different Linkers

The purpose of this study is to develop peptide-based platelet-derived growth factor receptor β (PDGFRβ) imaging probes and examine the effects of several linkers, namely un-natural amino acids (D-alanine and β-alanine) and ethylene-glycol (EG), on the properties of Ga-DOTA-(linker)-IPLPPPRRPFFK peptides. Seven radiotracers, ⁶⁷Ga-DOTA-(linker)-IPLPPPRRPFFK peptides, were designed, synthesized, and evaluated. The stability and cell uptake in PDGFRβ positive peptide cells were evaluated in vitro. The biodistribution of [⁶⁷Ga]Ga-DOTA-EG₂-IPLPPPRRPFFK ([⁶⁷Ga]27) and [⁶⁷Ga]Ga-DOTA-EG₄-IPLPPPRRPFFK ([⁶⁷Ga]28), which were selected based on in vitro stability in murine plasma and cell uptake rates, were determined in BxPC3-luc-bearing nu/nu mice. Seven ⁶⁷Ga-labeled peptides were successfully synthesized with high radiochemical yields (>85%) and purities (>99%). All evaluated radiotracers were stable in PBS (pH 7.4) at 37 °C. However, only [⁶⁷Ga]27 and [⁶⁷Ga]28 remained more than 75% after incubation in murine plasma at 37 °C for 1 h. [⁶⁷Ga]27 exhibited the highest BxPC3-luc cell uptake among the prepared radiolabeled peptides. As regards the results of the biodistribution experiments, the tumor-to-blood ratios of [⁶⁷Ga]27 and [⁶⁷Ga]28 at 1 h post-injection were 2.61 ± 0.75 and 2.05 ± 0.77, respectively. Co-injection of [⁶⁷Ga]27 and an excess amount of IPLPPPRRPFFK peptide as a blocking agent can significantly decrease this ratio. However, tumor accumulation was not considered sufficient. Therefore, further probe modification is required to assess tumor accumulation for in vivo imaging.