Abstract Currently, the DFO chelator is commonly used to conjugate monoclonal antibodies (mAbs) and 89 Zr, whereas the DOTA chelator is commonly used to conjugate mAbs and alpha- and beta-emitting metal radionuclides. However, if the degradation of [ 89 Zr]Zr-DFO-mAb is not negligible, the in vivo biodistribution of 89 Zr might not reflect that of metal radionuclides conjugated with DOTA-mAb. We hypothesized that [ 89 Zr]Zr-DOTA-mAb as a new imaging counterpart would accurately predict the biodistribution of therapeutic metal radionuclides delivered by DOTA-mAb. In this study, we prepared [ 89 Zr]Zr-DOTA-trastuzumab for the first time by a two-step reaction using click chemistry and then investigated the differences in biodistribution profiles between two chelating approaches for 89 Zr. Methods We prepared [ 89 Zr]Zr-DOTA-trastuzumab from DOTA-tetrazine conjugates (DOTA-Tz) and transcyclooctene-trastuzumab conjugates (TCO-trastuzumab). We first radiolabeled DOTA-Tz with 89 Zr in a reaction solution of MeOH and HEPES buffer and then used a click reaction to obtain [ 89 Zr]Zr-DOTA-Tz/TCO-trastuzumab. We performed biodistribution studies and PET imaging with [ 89 Zr]Zr-DOTA-trastuzumab in a mouse model of HER2-positive ovarian cancer, SKOV3 xenograft mice at 24, 72, and 144 hours post-injection and compared these data with those of [ 89 Zr]Zr-DFO-trastuzumab. Results TCO-trastuzumab was radiolabeled with [ 89 Zr]Zr-DOTA-Tz in the two-step reaction in good radiochemical yield (57.8 ± 17.6%). HER2-positive tumors were clearly visualized with [ 89 Zr]Zr-DOTA-trastuzumab in PET imaging studies. The temporal profile changes of 89 Zr radioactivity in SKOV3 tumors and bone marrow were sufficiently different between [ 89 Zr]Zr-DOTA-trastuzumab and [ 89 Zr]Zr-DFO-trastuzumab (P < 0.05). Conclusion: [ 89 Zr]Zr-DOTA-trastuzumab can be produced by the two-step radiolabeling reaction based on the Tz/TCO click reaction. Presumably, 89 Zr released from DFO is not negligible. In contrast, [ 89 Zr]Zr-DOTA-mAb would better predict the biodistribution of [ 177 Lu]Lu- or [ 225 Ac]Ac-DOTA-mAb than [ 89 Zr]Zr-DFO-mAb, thus avoiding the use of different chelator for 89 Zr at the expense of the click chemistry step. Graphical Abstract
Abstract A mild and facile Wittig reaction between N ‐substituted maleimides and aldehydes has been developed. Various synthetically valuable alkylidenesuccinimides were obtained from this one‐pot reaction in high yields (up to 99%). The product was obtained by simple filtration and no extra purification was necessary. Ethanol, an environment‐benign solvent, was found to be a suitable reaction medium.
The asymmetric allylic alkylation of Morita-Baylis-Hillman (MBH) carbonates with allyl ketones has been developed. The α-regioselective alkylation adducts, containing a hexa-1,5-diene framework with important synthetic value, were achieved in up to 83% yield, >99% ee, and 50:1 dr by using a commercially available Cinchona alkaloid as the catalyst. From the allylic alkylation adduct, a cyclohexene bearing two adjacent chiral centers was readily prepared.
Selective substitutions of Fe 2 ( μ ‐odt)(CO) 6 (odt = 1,3‐oxadithiolate, A ) and small bite‐angle diphosphines (Ph 2 P) 2 X [X = CH 2 (dppm) or N (CH 2 CHMe 2 ) (dppa)] have been well investigated in this study. With Me 3 NO·2H 2 O in MeCN at room temperature, the reaction of A and dppm produced the monodentate complex [Fe 2 ( μ ‐odt)(CO) 5 ( κ 1 ‐dppm)] ( 1 ), whereas the similar reaction with dppa afforded the chelate complex [Fe 2 ( μ ‐odt)(CO) 4 ( κ 2 ‐dppa)] ( 2 ). Using UV irradiation in toluene emitting at 365 nm, the treatment of A and dppm rarely resulted in the formation of the bridge complex [Fe 2 ( μ ‐odt)(CO) 4 ( μ ‐dppm)] ( 3 ), whereas the similar treatment with dppa formed the chelate complex 2 . Under thermolysis condition, refluxing solution of A with dppm or dppa gave the bridge complex 3 and [Fe 2 ( μ ‐odt)(CO) 4 ( μ ‐dppa)] ( 4 ), respectively, in which the former was formed in toluene (110 °C) but the latter was produced in xylene (138 °C). All the new complexes 1 – 4 obtained above were characterized by element analysis, FT‐IR, NMR ( 1 H, 31 P) spectroscopies, and particularly for 1 – 3 by X‐ray crystallography. Furthermore, the in situ protonations of 2 with a weak acid HOAc (acetic acid) and a strong acid TFA (trifluoroacetic acid) are explored by means of FT‐IR and NMR ( 1 H, 31 P) spectra. In addition, the electrochemical behaviors of 2 – 4 are studied and compared through cyclic voltammetry (CV) in the absence and presence of a strong acid (TFA) as a proton source, indicating that they all are active for electrocatalytic proton reduction to hydrogen (H 2 ).
A Lewis base catalyzed allylic hydroxylation of Morita-Baylis-Hillman (MBH) carbonates has been developed. Various chiral MBH alcohols can be synthesized in high yields (up to 99%) and excellent enantioselectivities (up to 94% ee). This is the first report using water as a nucleophile in asymmetric organocatalysis. The nucleophilic role of water has been verified using (18)O-labeling experiments.
Novel caged intramolecular ketals of β‐C‐glycosidic ketones were prepared from pyranoses. The structures of the new compounds were elucidated by NMR and HRMS spectral analysis. Preliminary studies revealed that the intramolecular ketal could be used to protect 3‐ and 6‐hydroxyl groups of β‐C‐glycosidic ketones.
ObjectiveA family history of a chronic disease often predicts disease risk, with predictive value determined by heritability, the proportion of variation in risk explained by inherited genetic factors. Our objective was to assess the validity of disease heritability estimates from electronic healthcare records (EHRs) that capture family relationships and disease diagnoses. ApproachA population-based investigation was conducted using healthcare records from Manitoba, Canada for 1970 to 2021. We constructed family relationships for up to four generations using health insurance registration information containing unique family and individual identifiers. Health histories for family members were created using diagnosis codes in hospital and physician visit records. Linear mixed-effects models were used to estimate heritability (h) for 130 chronic health conditions using open-source Clinical Classifications Software that defines clinically-meaningful disease categories. Comparisons between EHR-derived estimates and genetically-derived estimates from published studies were used to assess validity of the methodology. ResultsHealth insurance registration data were used to construct 10,000 families that included 116,879 individuals. Median family size was 9 (interquartile range: 8). Median observation time was 39.6 years (interquartile range: 25.7). Males comprised half (51.0%) of family members. A total of 272,114 familial relationships were identified; slightly more than half (53%) were first degree (i.e., child and parent) relationships. One-third (33.2%) of families were comprised of four generations; only 15.3% were comprised of two generations. Heritability estimates were consistent with published genetically-derived estimates for several conditions, including diabetes (EHR h = 0.29 vs. 0.22), anemia (EHR h = 0.21 vs. 0.20), and asthma (EHR h = 0.34 vs. 0.33). However, inconsistencies were identified for pancreatic disorders, gastrointestinal conditions, some mental health conditions, and heart disease. ConclusionEHRs provide a promising approach to explore heritability of selected health conditions in large, diverse populations. Inconsistencies between EHR-derived and genetically-derived estimates are indicative of the limitations of diagnoses recorded for administrative purposes. Future research will explore sex-specific heritability estimates and effects of change in disease diagnosis coding over time.
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