Design, Synthesis, and Evaluation of ¹⁸F-Labeled Tracers Targeting Fibroblast Activation Protein for Brain Imaging

Abstract

Fibroblast activation protein (FAP) is closely related to central nervous system diseases such as stroke and brain tumors, but PET tracers that can be used for brain imaging have not been reported. Here, we designed, synthesized, and evaluated 18F-labeled UAMC1110 derivatives suitable for brain imaging targeting FAP. By substituting the F atom for the H atom on the aromatic ring of compound UAMC1110, 1a–c were designed and prepared. 1a–c were confirmed to have a high affinity for FAP through molecular docking and enzyme assay. [ 18 F]1a–c were successfully prepared and confirmed to have high affinity. The stability in vivo indicates that no obvious metabolites of [ 18 F]­1a,b were found in the plasma 1 h after injection, which is beneficial for brain imaging. In vitro cell uptake experiments showed that [ 18 F]­1a,b and [68Ga]­FAPI04 exhibited similar uptake and internalization rates. PET imaging of U87MG subcutaneous tumor showed that [ 18 F]­1a,b could penetrate the blood–brain barrier with higher uptake and longer retention time than [68Ga]­FAPI04 (uptake at 62.5 min, 1.06 ± 0.23, 1.09 ± 0.25% ID/g vs 0.21 ± 0.10% ID/g, respectively). The brain-to-blood ratios of [ 18 F]­1a,b were better than [68Ga]­FAPI04. Biodistribution and PET imaging showed that [ 18 F]­1a had better uptake on tumors and a higher tumor-to-muscle ratio than [ 18 F]­1b and [68Ga]­FAPI04. Further imaging of U87MG intracranial glioma showed that [ 18 F]­1a outlined high-contrast gliomas in a short period of time compared to [ 18 F]­1b. Therefore, [ 18 F]­1a is expected to be useful in the diagnosis of FAP-related brain diseases.

18F-Labeled PET Tracers Specific for Adenosine A2A Receptor: Design, Synthesis, and Biological Evaluation

“…The radiochemical yields of [ 18 F]­MNI-444, [ 18 F]­3 , and [ 18 F]­BIBD-399 were approximately 15%. Following the previously reported methods (Scheme S2), 13b failed to convert to [ 18 F]­12c . We tried to use other leaving groups such as trimethyltin and nitro, but [ 18 F]­12c was still not available.…”

“…Crystal 1 exhibits a planar rigid skeleton, which is similar to the ligand (ZMA) conformation in the A 2A R crystal complex (PDB code: 3RFM). , The planar rigid skeleton makes it easy to form parallel or vertical π–π stacking interactions with the key amino acid residues of A 2A R, which is beneficial for enhancing the affinity of newly designed tracers to A 2A R. Compound 1 reacts with the deuterated ethylenedisulfonyl ester to obtain the labeled precursor 2 (Scheme ). Precursor 2 is fluorinated to obtain 3 .…”

“…The adenosine A 2A R crystal complex structure (PDB ID: 5NLX and 3RFM) was downloaded from the Protein Data Bank. ZMA was extracted from the crystal complex, , and the receptor and ligands were sequentially treated with AutoDockTools-1.5.6 (Scripps Research Institute) and Chem3D Pro 14.0 software (CambridgeSoft), respectively. Docking experiments were performed using AutoDock Vina (Scripps Research Institute) .…”

Design, Synthesis, and Evaluation of [18F]BIBD-300 as a Positron Emission Tomography Tracer for Poly(ADP-Ribose) Polymerase-1

“… According to the radiolabeling method of [ 18 F]FTT, [ 18 F]8a , [ 18 F]8d , [ 18 F]8j , and [ 18 F]BIBD-300 were all successfully obtained with radiolabeling yields greater than 15% (Schemes and S1–S3), Figures S1–3 and S5–6). [ 18 F]8g was prepared using a reported method with a radiolabeling yield of 10% (Scheme S4 and Figure S4). The specific activity of [ 18 F]8a , [ 18 F]8d , [ 18 F]8g , [ 18 F]FTT, or [ 18 F]BIBD-300 was >120 MBq/nmol ( n = 3) at the end of radiosynthesis.…”

“…Finally, a formulated solution of [ 18 F]­8a , [ 18 F]­8d , [ 18 F]­8j , [ 18 F]­FTT, or [ 18 F]­BIBD-300 ready for administration was obtained. The radiolabeling method for [ 18 F]­8g follows the trimethyltin radiolabeling method we have reported …”