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The design and radiosynthesis of [ 18 F]NT376, a high potency inhibitor of class-IIa histone deacetylases (HDAC) is reported. We utilized a three-step radiochemical approach that led to the radiosynthesis of [ 18 F]NT376 in a good radiochemical yield, (17.0 ± 3%, decay corrected), high radiochemical purity (> 97%) and relatively high molar activity of 185.0 GBq/µmol (> 5.0 Ci/µmol). The repositioning of the 18 F-radiolabel into a phenyl ring ( 18 F-Fluoro-aryl) of the class-IIa HDAC inhibitor avoided the shortcomings of the direct radiolabeling of the 5-trifluoromethyl-1,2,4-oxadiazole moiety that was reported by us previously and was associated with low molar activity (0.74-1.51 GBq/µmol, 20-41 mCi/µmol). This radiochemical approach could find a wider application for radiolabeling similar molecules with good radiochemical yield and high molar activity., (© 2024. The Author(s).)

Herein, we describe the design, synthesis and deciphering of the key characteristics of the structure activity relationship (SAR) of trifluoromethyloxadiazole (TFMO) bearing class-IIa HDAC inhibitors. Our medicinal chemistry campaign of 23 compounds identified compound 1 as a highly potent inhibitor with sub nM affinity to class-IIa HDAC4 isoform. Therefore, We radiolabeled compound 1 (named thereafter as NT160) with [ 18 F]fluoride thus producing the identical [ 18 F]-NT160 as a diagnostic tool for positron emission tomography (PET). [ 18 F]-NT160 was produced in high radiochemical purity (>95%), moderate radiochemical yield (2-5%) and moderate molar activity in the range of 0.30-0.85 GBq/umol (8.0-23.0 mCi/umol). We also established that [ 18 F]-NT160 can cross the blood brain barrier and bind to class-IIa HDACs in vivo. The combination of [ 18 F]-NT160 and 1 represent a novel theranostic pair using the same molecule to enable diagnostic PET imaging with [ 18 F]-NT160 followed by targeted therapy with NT160., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Small molecules that contain the (TFMO) moiety were reported to specifically inhibit the class-IIa histone deacetylases (HDACs), an important target in cancer and the disorders of the central nervous system (CNS). However, radiolabeling methods to incorporate the [18F]fluoride into the TFMO moiety are lacking. Herein, we report a novel late-stage incorporation of [18F]fluoride into the TFMO moiety in a single radiochemical step. In this approach the bromodifluoromethyl-1,2,4-oxadiazole was converted into [18F]TFMO via no-carrier-added bromine-[18F]fluoride exchange in a single step, thus producing the PET tracers with acceptable radiochemical yield (3-5%), high radiochemical purity (> 98%) and moderate molar activity of 0.33-0.49 GBq/umol (8.9-13.4 mCi/umol). We validated the utility of the novel radiochemical design by the radiosynthesis of [18F]TMP195, which is a known TFMO containing potent inhibitor of class-IIa HDACs.

Sirtuin 1 (SIRT1) is a class III histone deacetylase that plays significant roles in the regulation of lifespan, metabolism, memory, and circadian rhythms and in the mechanisms of many diseases. However, methods of monitoring the pharmacodynamics of SIRT1-targeted drugs are limited to blood sampling because of the invasive nature of biopsies. For the noninvasive monitoring of the spatial and temporal dynamics of SIRT1 expression-activity in vivo by PET-CT-MRI, we developed a novel substrate-type radiotracer, [ 18 F]-2-fluorobenzoylaminohexanoicanilide (2-[ 18 F]BzAHA). PET-CT-MRI studies in rats demonstrated increased accumulation of 2-[ 18 F]BzAHA-derived radioactivity in the hypothalamus, hippocampus, nucleus accumbens, and locus coeruleus, consistent with autoradiographic and immunofluorescent (IMF) analyses of brain-tissue sections. Pretreatment with the SIRT1 specific inhibitor, EX-527 (5 mg/kg, ip), resulted in about a 20% reduction of 2-[ 18 F]BzAHA-derived-radioactivity accumulation in these structures. In vivo imaging of SIRT1 expression-activity should facilitate studies that improve the understanding of SIRT1-mediated regulation in the brain and aid in the development and clinical translation of SIRT1-targeted therapies.

Purpose: The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-invasive PET imaging of epigenetic regulatory processes mediated by SIRT2 in normal and disease tissues., Procedures: A library of compounds containing tert-butyloxycarbonyl-lysine-aminomethylcoumarin backbone was derivatized with fluoroalkyl chains 3-16 carbons in length. SIRT2 most efficiently cleaved the myristoyl, followed by 12-fluorododecanoic and 10-fluorodecanoic groups (K cat /K m 716.5 ± 72.8, 615.4 ± 50.5, 269.5 ± 52.1/s mol, respectively). Radiosynthesis of 12- [ 18 F]fluorododecanoic aminohexanoicanilide (12-[ 18 F]DDAHA) was achieved by nucleophilic radiofluorination of 12-iododecanoic-AHA precursor., Results: A significantly higher accumulation of 12-[ 18 F]DDAHA was observed in MCF-7 and MDA-MB-435 cells in vitro as compared to U87, MiaPaCa, and MCF10A, which was consistent with levels of SIRT2 expression. Initial in vivo studies using 12-[ 18 F]DDAHA conducted in a 9L glioma-bearing rats were discouraging, due to rapid defluorination of this radiotracer upon intravenous administration, as evidenced by significant accumulation of F-18 radioactivity in the skull and other bones, which confounded the interpretation of images of radiotracer accumulation within the tumor and other regions of the brain., Conclusions: The next generation of SIRT2-specific radiotracers resistant to systemic defluorination should be developed using alternative sites of radiofluorination on the aliphatic chain of DDAHA. A SIRT2-selective radiotracer may provide information about SIRT2 expression and activity in tumors and normal organs and tissues, which may help to better understand the roles of SIRT2 in different diseases.

Introduction: Earlier, we reported syntheses of ethyl-β-D-galactopyranosyl-(1,4')-2'-deoxy-2'-[(18)F]fluoro-β-D-glucopyranoside (Et-[(18)F]FDL) and 1'-[(18)F]fluoroethyl-β-D-lactose ([(18)F]-FEL) for positron emission tomography (PET) of pancreatic carcinoma. Et-[(18)F]FDL requires a precursor, which involves 11 steps to synthesize and produces overall low yields. Synthesis of precursors for [(18)F]-FEL requires four steps, but those precursors produced low radiochemical yields. Here, we report new precursors and an improved synthesis of [(18)F]-FEL., Method: Two precursors, 1'-(methanesulfonyl)ethyl-2',3',6',2,3,4,6-hepta-O-acetyl-β-D-lactose 2a and 1'-(p-nitrophenyl-sulfonyl)ethyl-2',3',6',2,3,4,6-hepta-O-acetyl-β-D-lactose 2b, were synthesized from lactose in four steps. Radiofluorination reactions were performed using K(18)F/kryptofix and the crude product [(18)F]-3 was purified by HPLC. Basic hydrolysis of [(18)F]-3 produced 1'-[(18)F]fluoroethyl-β-D-lactose [(18)F]-4, which was neutralized, diluted with saline, filtered on a 0.22-µm filter, and analyzed by radio-TLC., Results: The average radiochemical yields of [(18)F]-4 (d. c.) from 2a and 2b were 21% (n = 6) and 65% (n = 6), respectively, with >99% radiochemical purity and specific activity of 55.5 GBq/µmol. Synthesis time was 90-95 min from the end of bombardment., Conclusion: An improved synthesis of [(18)F]FEL has been achieved in high yields, with high purity and specific activity. Precursor 2b with this method should be applicable for high yield automated production in a commercial synthesis module for clinical application., (Copyright © 2013 John Wiley & Sons, Ltd.)

Purpose: We have incorporated a positron emission tomography (PET) functionality in T cells expressing a CD19-specific chimeric antigen receptor (CAR) to non-invasively monitor the adoptively transferred cells.Procedures: We engineered T cells to express CD19-specific CAR, firefly luciferase (ffLuc), and herpes simplex virus type-1 thymidine kinase (TK) using the non-viral-based Sleeping Beauty (SB) transposon/transposase system adapted for human application. Electroporated primary T cells were propagated on CD19+ artificial antigen-presenting cells.Results: After 4 weeks, 90 % of cultured cells exhibited specific killing of CD19+ targets in vitro, could be ablated by ganciclovir, and were detected in vivo by bioluminescent imaging and PET following injection of 2'-deoxy-2'-[18F]fluoro-5-ethyl-1-β-D-arabinofuranosyl-uracil ([18F]FEAU).Conclusion: This is the first report demonstrating the use of SB transposition to generate T cells which may be detected using PET laying the foundation for imaging the distribution and trafficking of T cells in patients treated for B cell malignancies. [ABSTRACT FROM AUTHOR]