Automated synthesis of PET radiotracers by copper‐mediated <sup>18</sup>F‐fluorination of organoborons: Importance of the order of addition and competing protodeborylation

Mossine, Andrew V.; Brooks, Allen F.; Bernard‐Gauthier, Vadim; Bailey, Justin J.; Ichiishi, Naoko; Schirrmacher, Ralf; Sanford, Melanie S.; Scott, Peter J. H.

doi:10.1002/jlcr.3583

Cited by 41 publications

(49 citation statements)

References 21 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our in vitro data showed that 2 is a potential inhibitor of PARP1, 2 and 3 isoforms with similar IC 50 compared with [ 19 F]AZD2461 1. This underlines the necessity of HPLC separation to avoid any contamination [17,32]. With 19 F references 1 and 2 in hand, we were able to demonstrate the efficient separation of both products by semi-preparative and analytical radio-HPLC, affording a difference in retention time of 3 min between both products.…”

Section: Discussionmentioning

confidence: 61%

[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

et al. 2020

View full text Add to dashboard Cite

Background Poly (ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1–3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP3, and to investigate its potential for PARP targeting in vivo. Methods Using the Cu-mediated 18F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the 18F-labelled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [18F]AZD2461 in vitro was assessed in a range of pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP expression and in vivo in xenograft-bearing mice. Blocking experiments were performed with both olaparib and AZD2461. Results [18F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9 % ± 3 % and 3 % ± 1 % activity yields non-decay corrected). [18F]AZD2461 was taken up in vivo in PARP1-expressing tumours, and the highest uptake was observed for PSN-1 cells (7.34 ± 1.16 %ID/g). In vitro blocking experiments showed a lesser ability of olaparib to reduce [18F]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461. Conclusion Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents.

show abstract

Section: Discussionmentioning

confidence: 61%

[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Starting from 2.6 to 13.1 GBq of [ 18 F]F − , [ 18 F]FOMPyD was reliably obtained in an 8.7±2.8% decay‐corrected radiochemical yield, an effective molar activity (A m ) of 187±93 GBq/μmol and with a radiochemical purity >99% (n = 4). Importantly, the tracer was free from the unreacted 6 and other nonradioactive impurities, including the product of the protodeboronation reaction 5‐(4‐(benzyloxy)‐3‐methoxybenzyl)pyrimidine‐2,4‐diamine (BOMPyD; Figure ), a known major side‐product in this reaction (Figure S1). This procedure represents a major improvement over the previously reported four‐step sequence and, for the first time, allowed for preclinical evaluation of [ 18 F]FOMPyD by in vitro autoradiography in human and rat post‐mortem brain tissues and in vivo PET imaging in wild‐type rats.…”

Section: Resultsmentioning

confidence: 99%

Efficient radiosynthesis and preclinical evaluation of [¹⁸F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging

Singleton

Bdair

Bailey

et al. 2020

Labelled Comp Radiopharmac

Self Cite

View full text Add to dashboard Cite

Herein we report an efficient radiolabeling of a 18F‐fluorinated derivative of dual inhibitor GW2580, with its subsequent evaluation as a positron emission tomography (PET) tracer candidate for imaging of two neuroreceptor targets implicated in the pathophysiology of neurodegeneration: tropomyosin receptor kinases (TrkB/C) and colony stimulating factor receptor (CSF‐1R). [18F]FOMPyD was synthesized from a boronic acid pinacolate precursor via copper‐mediated 18F‐fluorination concerted with thermal deprotection of the four Boc groups on a diaminopyrimidine moiety in an 8.7±2.8% radiochemical yield, a radiochemical purity >99%, and an effective molar activity of 187±93 GBq/μmol. [18F]FOMPyD showed moderate brain permeability in wild‐type rats (SUVmax = 0.75) and a slow washout rate. The brain uptake was partially reduced (ΔAUC40–90 = 11.6%) by administration of the nonradioactive FOMPyD (up to 30 μg/kg). In autoradiography, [18F]FOMPyD exhibits ubiquitous distribution in rat and human brain tissues with relatively high nonspecific binding revealed by self‐blocking experiment. The binding was blocked by TrkB/C inhibitors, but not with a CSF‐1R inhibitor, suggesting selective binding to the former receptor. Although an unfavorable pharmacokinetic profile will likely preclude application of [18F]FOMPyD as a PET tracer for brain imaging, the concomitant one‐pot copper‐mediated 18F‐fluorination/Boc‐deprotection is a practical technique for the automated radiosynthesis of acid‐sensitive PET tracers.

show abstract

“…During the 18 F-fluorination, the protodeboronation product was formed which reduced the effective A m to a low value of 15 GBq/µmol, an order of magnitude below what was expected. After extensive screening, this problem could be solved by employing a pentafluorophenyl (PFP) HPLC column for tracer purification—which constitutes currently the standard method used to achieve separation [65]. The column material showed improved stationary phase affinity interaction with the fluorinated TRACK tracer over standard octadecylsilane reversed phase, leading to a base-line separation of [ 18 F]TRACK from all impurities—including the protodeboronation side product.…”

Section: The Development Of Trk Radioligands For Pet Imagingmentioning

confidence: 99%

Radioligands for Tropomyosin Receptor Kinase (Trk) Positron Emission Tomography Imaging

et al. 2019

Self Cite

View full text Add to dashboard Cite

The tropomyosin receptor kinases family (TrkA, TrkB, and TrkC) supports neuronal growth, survival, and differentiation during development, adult life, and aging. TrkA/B/C downregulation is a prominent hallmark of various neurological disorders including Alzheimer’s disease (AD). Abnormally expressed or overexpressed full-length or oncogenic fusion TrkA/B/C proteins were shown to drive tumorigenesis in a variety of neurogenic and non-neurogenic human cancers and are currently the focus of intensive clinical research. Neurologic and oncologic studies of the spatiotemporal alterations in TrkA/B/C expression and density and the determination of target engagement of emerging antineoplastic clinical inhibitors in normal and diseased tissue are crucially needed but have remained largely unexplored due to the lack of suitable non-invasive probes. Here, we review the recent development of carbon-11- and fluorine-18-labeled positron emission tomography (PET) radioligands based on specifically designed small molecule kinase catalytic domain-binding inhibitors of TrkA/B/C. Basic developments in medicinal chemistry, radiolabeling and translational PET imaging in multiple species including humans are highlighted.

show abstract

Automated synthesis of PET radiotracers by copper‐mediated ¹⁸F‐fluorination of organoborons: Importance of the order of addition and competing protodeborylation

Cited by 41 publications

References 21 publications

[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

Efficient radiosynthesis and preclinical evaluation of [¹⁸F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging

Radioligands for Tropomyosin Receptor Kinase (Trk) Positron Emission Tomography Imaging

Contact Info

Product

Resources

About

Automated synthesis of PET radiotracers by copper‐mediated 18F‐fluorination of organoborons: Importance of the order of addition and competing protodeborylation

Cited by 41 publications

References 21 publications

[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

Efficient radiosynthesis and preclinical evaluation of [18F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging

Radioligands for Tropomyosin Receptor Kinase (Trk) Positron Emission Tomography Imaging

Contact Info

Product

Resources

About

Automated synthesis of PET radiotracers by copper‐mediated ¹⁸F‐fluorination of organoborons: Importance of the order of addition and competing protodeborylation

Efficient radiosynthesis and preclinical evaluation of [¹⁸F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging