¹⁸F-Fluorination of Unactivated C–H Bonds in Branched Aliphatic Amino Acids: Direct Synthesis of Oncological Positron Emission Tomography Imaging Agents

Abstract

A mild and selective photocatalytic C-H F-fluorination reaction has been developed that provides direct access toF-fluorinated amino acids. The biodistribution and uptake of three F-labeled leucine analogues via LAT1 mediated transport in several cancer cell lines is reported. Positron emission tomography imaging of mice bearing PC3 (prostate) or U87 (glioma) xenografts using 5-[F]-fluorohomoleucine showed high tumor uptake and excellent tumor visualization, highlighting the utility of this strategy for rapid tracer discovery for oncology.

Site‐Selective, Late‐Stage C−H 18F‐Fluorination on Unprotected Peptides for Positron Emission Tomography Imaging

“…As summarized in Figure 4, we observed excellent radiochemical conversion (RCC) in the 18 F-fluorination of dipeptides,p roducing the 18 F-labelled dipeptides 24-27 with no detectable epimerization or fluorination at other sites.The radiochemical yield (RCY,d ecay corrected from [ 18 F]NFSI) for these processes were comparable or better than those reported previously by us for the radiofluorination of branched aliphatic amino acids. [20] We next demonstrated the radiofluorination on as mall series of Leu-containing tetrapeptides,and in each case the RCC was > 25 %and 18 Flabelled tetrapeptides 28-30 were isolated in RCYs ranging from 16 to 35 %. TheEGFRvIII-targeting peptide FALGEA-NH 2 [30] was also directly radiofluorinated providing [ 18 F]FAfLGEA-NH 2 (31)( RCC % 10 %) after % 80 min total radiosynthesis time.This last result compares well to previous labelling studies of FALGEA-NH 2 that involved coupling with the [ 18 F]fluorobenzoic acid ([ 18 F]FBA) prosthetic group and proceeded with RCYs ranging from of 2.6-9.8 %( decay corrected) after a3hr adiosynthesis.…”

“…[35] Importantly,a nalysis of the biodistribution of [ 18 F]ZJ-43 (32)i nh ealthy mice showed low bone accumulation (1.7 %I Dg À1 )s uggesting that the peptidic [ 18 F]fluoroleucine fragment is not susceptible to the same degradation pathways of [ 18 F]fluoroleucine itself,w hich displays significant bone accumulation (11.9 %I Dg À1 ). [20] While the specific activity (SA) of 18 F-labelled peptides 24-33 produced in this study ranged from 1.3-5.3 MBq mmol À1 , significant improvements in SA can be achieved by lengthening the proton irradiation time on [ 18 O]O 2 .M oroever, [ 18 F]F 2 with SAs up to 55 GBq mmol À1 can be prepared using ap rocess described by Bergman and Solin, [36] and [ 18 F]NFSI produced via this method has aSAof10.3 GBq mmol À1 . [37] In summary, we have developedaversatilea nd direct, aqueousa pproachf or radiofluorinationo fu nprotectedL eucontaining peptides that does notr elyo np rosthetic groups.…”

Chemie der Positronenemissionstomographie: Aktuelle Fortschritte bei 11C‐, 18F‐, 13N‐ und 15O‐Markierungsreaktionen

“…2017 berichteten Britton, Schaffer, Bénard, Martin et al. über eine selektive photokatalytische 18 F‐Fluorierung von nicht‐aktivierten C‐H‐Bindungen mit [ 18 F]NFSI (Schema C) . Die Reaktion wurde durch eine H‐Abstraktion von der aliphatischen Kette unter Verwendung eines photoaktivierten Decawolframat‐Katalysators initiiert, woran sich ein [ 18 F]Fluoratomtransfer vom [ 18 F]NFSI anschloss.…”

Chemistry for Positron Emission Tomography: Recent Advances in 11C‐, 18F‐, 13N‐, and 15O‐Labeling Reactions

“…[204] The analogous reaction was also applied in the electrophilic 18 Ffluorination of electron-deficient fluorinated alkenes,such as [ 18 F]EF5 (Scheme 35 A2). [207] In 2015, Gouverneur and co-workers developed an organocatalyst-mediated enantioselective 18 F-fluorination of aldehydes with [ 18 F]NFSI (Scheme 35 B).…”