Radiosynthesis and First Preclinical Evaluation of the Novel 11C-Labeled FAP Inhibitor 11C-FAPI: A Comparative Study of 11C-FAPIs and (68Ga) Ga-DOTA-FAPI-04 in a High-FAP-Expression Mouse Model.

PURPOSE: 68Ga-labeled fibroblast activation protein inhibitors, such as [68Ga]Ga-DOTA-FAPI-04 and [68Ga]Ga-DOTA-FAPI-46, have been successfully applied in positron emission tomography imaging of various tumor types. To broaden the PET tracers of different positron nuclides for imaging studies of FAP-dependent diseases, we herein report the radiosynthesis and preclinical evaluation of two 11C-labeled FAP inhibitors, 11C-RJ1101 and 11C-RJ1102. METHODS: Two phenolic hydroxyl precursors based on a quinoline amide core coupled with a 2-cyanopyrrolidine moiety were coupled with [11C]CH3I to synthesize 11C-RJ1101 and 11C-RJ1102. In vivo small-animal PET and biological distribution studies of 11C-RJ1101 and 11C-RJ1102 compared to [68Ga]Ga-DOTA-FAPI-04 were conducted in nude mice bearing U87MG tumor xenografts at 30, 60, and 90min, respectively. RESULTS: 11C-RJ1101 and 11C-RJ1102 were synthesized in over 15% radiochemical yields, with specific activities of 67 GBq/µmol and 34 GBq/µmol, respectively, at the end of synthesis and radiochemical purities greater than 99%. In U87MG tumor xenograft PET studies, the three tracers experienced higher specific uptake at the tumor site. However, because of significant differences in metabolism and clearance, [68Ga]Ga-DOTA-FAPI-04 experienced high uptake in the kidney, whereas 11C-RJ1101 and 11C-RJ1102 showed high uptake in the liver and intestine. Biodistribution studies revealed significant hepatobiliary excretion of 11C-RJ1101 and 11C-RJ1102. 11C-RJ1102 showed higher specific tumor uptake in U87MG xenografts (1.71 ± 0.08% injected dose per Gram of tissue [ID/g]) than 11C-RJ1101 (1.34 ± 0.10%ID/g) and [68Ga]Ga-DOTA-FAPI-04 (1.29 ± 0.04%ID/g) after 30 min p. i. In orthotopic glioma models, the uptake values were 0.07 ± 0.03% ([68Ga]Ga-DOTA-FAPI-04) and 0.16 ± 0.03% (11C-RJ1102), respectively. CONCLUSION: 11C-RJ1101 and 11C-RJ1102 are interesting candidates for translation to the clinic, taking advantage of the shorter half-life and physical imaging properties of C-11.

Enantioselective Intermolecular Aminoalkynylation of Styrenes via Copper-Catalyzed Radical Relay.

A novel copper-catalyzed intermolecular aminoalkynylation of alkenes through a radical relay process has been developed in this work, in which N-fluoro-N-alkylsulfonamides (NFASs) are used as nitrogen-centered radical precursors and alkynyltrimethoxysilanes as alkynylating reagents. This method presents an efficient and straightforward approach to various enantioenriched 2-alkynyl-2-arylethylamines in good yields with excellent enantioselectivity, and these products can be readily converted into a series of synthetically useful chiral terminal alkynes, allenes, alkenes, amines, amino acids, and N-heterocycles.

The optimization of a novel selective antagonist for human M2 muscarinic acetylcholine receptor.

Muscarinic acetylcholine receptors (mAChRs) comprise five distinct subtypes denoted M1 to M5. The antagonism of M2 subtype could increase the release of acetylcholine from vesicles into the synaptic cleft and improve postsynaptic functions in the hippocampus via M1 receptor activation, displaying therapeutic potentials for Alzheimer's disease. However, drug development for M2 antagonists is still challenged among different receptor subtypes. In this study, by optimizing a scaffold from virtual screening, we synthesized two focused libraries and generated up to 50 derivatives. By measuring potency and binding selectivity, we discovered a novel M2 antagonist, ligand 47, featuring submicromolar IC50, high M2/M4 selectivity (~30-fold) and suitable lipophilicity (cLogP = 4.55). Further study with these compounds also illustrates the structure-activity relationship of this novel scaffold. Our study could not only provide novel lead structure, which was easy to synthesize, but also offer valuable information for further development of selective M2 ligands.