Delivering strong 1H nuclear hyperpolarization levels and long magnetic lifetimes through signal amplification by reversible exchange

Hyperpolarization turns typically weak NMR and MRI responses into strong signals so that ordinarily impractical measurements become possible. The potential to revolutionize analytical NMR and clinical diagnosis through this approach reflect this area's most compelling outcomes. Methods to optimize the low cost parahydrogen based approach signal amplification by reversible exchange (SABRE) with studies on a series of biologically relevant nicotinamides and methyl nicotinates are detailed. These procedures involve specific 2H-labelling in both the agent and catalyst and achieve polarization lifetimes of ca. 2 minutes with 50% polarization in the case of 4,6-d2-methylnicotinate. As a 1.5 T hospital scanner has an effective 1H polarization level of just 0.0005% this strategy should result in compressed detection times for chemically discerning measurements that probe disease. To demonstrate this techniques generality, we exemplify further studies on a range of pyridazine, pyrimidine, pyrazine and isonicotinamide analogues that feature as building blocks in biochemistry and many disease treating drugs

Improving the hyperpolarization of (31)p nuclei by synthetic design

Traditional (31)P NMR or MRI measurements suffer from low sensitivity relative to (1)H detection and consequently require longer scan times. We show here that hyperpolarization of (31)P nuclei through reversible interactions with parahydrogen can deliver substantial signal enhancements in a range of regioisomeric phosphonate esters containing a heteroaromatic motif which were synthesized in order to identify the optimum molecular scaffold for polarization transfer. A 3588-fold (31)P signal enhancement (2.34% polarization) was returned for a partially deuterated pyridyl substituted phosphonate ester. This hyperpolarization level is sufficient to allow single scan (31)P MR images of a phantom to be recorded at a 9.4 T observation field in seconds that have signal-to-noise ratios of up to 94.4 when the analyte concentration is 10 mM. In contrast, a 12 h 2048 scan measurement under standard conditions yields a signal-to-noise ratio of just 11.4. (31)P-hyperpolarized images are also reported from a 7 T preclinical scanner

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Improving the Hyperpolarization of ³¹P Nuclei by Synthetic Design

Traditional ³¹P NMR or MRI measurements suffer from low sensitivity relative to ¹H detection and consequently require longer scan times. We show here that hyperpolarization of ³¹P nuclei through reversible interactions with <i>para</i>hydrogen can deliver substantial signal enhancements in a range of regioisomeric phosphonate esters containing a heteroaromatic motif which were synthesized in order to identify the optimum molecular scaffold for polarization transfer. A 3588-fold ³¹P signal enhancement (2.34% polarization) was returned for a partially deuterated pyridyl substituted phosphonate ester. This hyperpolarization level is sufficient to allow single scan ³¹P MR images of a phantom to be recorded at a 9.4 T observation field in seconds that have signal-to-noise ratios of up to 94.4 when the analyte concentration is 10 mM. In contrast, a 12 h 2048 scan measurement under standard conditions yields a signal-to-noise ratio of just 11.4. ³¹P-hyperpolarized images are also reported from a 7 T preclinical scanner

Hyperpolarisation through reversible interactions with parahydrogen

We describe here how the complexes Ir(COD)(NHC)Cl [NHC = IMes, SIMes, IPr, SIPr, ICy, IMe and ImMe2NPri2] provide significant insight into the catalytic process that underpins the hyperpolarization method signal amplification by reversible exchange (SABRE). These complexes react with pyridine and H2 to produce [Ir(H)2(NHC)(py)3]Cl which undergo ligand exchange on a timescale commensurate with good catalytic activity for the signal amplification by reversible exchange effect. This activity results from hydride ligand magnetic inequivalence and is highly dependent on the NHC. Variable temperature and kinetic studies demonstrate that rates of ligand loss which lie between 0.1 and 0.5 s−1 are ideal for catalysis. A role for the solvent complex [Ir(H)2(MeOH)(NHC)(py)2]Cl, which contains chemically inequivalent hydride ligands is revealed in the ligand exchange pathway. By optimisation of the conditions and NHC, a 5500-fold total pyridine signal enhancement is revealed when the NHC is IMes. Both T1-reduction effects and HD exchange with the solvent are probed and shown to link to catalyst efficiency. The resulting signal enhancements suggest future in vivo MRI measurements under physiological conditions using this catalytic effect will be possible

Toward Biocompatible Nuclear Hyperpolarization Using Signal Amplification by Reversible Exchange: Quantitative in Situ

[Image: see text] Signal amplification by reversible exchange (SABRE) of a substrate and parahydrogen at a catalytic center promises to overcome the inherent insensitivity of magnetic resonance. In order to apply the new approach to biomedical applications, there is a need to develop experimental equipment, in situ quantification methods, and a biocompatible solvent. We present results detailing a low-field SABRE polarizer which provides well-controlled experimental conditions, defined spins manipulations, and which allows in situ detection of thermally polarized and hyperpolarized samples. We introduce a method for absolute quantification of hyperpolarization yield in situ by means of a thermally polarized reference. A maximum signal-to-noise ratio of ∼10(3) for 148 μmol of substance, a signal enhancement of 10(6) with respect to polarization transfer field of SABRE, or an absolute (1)H-polarization level of ≈10(–2) is achieved. In an important step toward biomedical application, we demonstrate (1)H in situ NMR as well as (1)H and (13)C high-field MRI using hyperpolarized pyridine (d(3)) and (13)C nicotinamide in pure and 11% ethanol in aqueous solution. Further increase of hyperpolarization yield, implications of in situ detection, and in vivo application are discussed