Update on PET Tracer Development for Muscarinic Acetylcholine Receptors

Abstract

The muscarinic cholinergic system regulates peripheral and central nervous system functions, and, thus, their potential as a therapeutic target for several neurodegenerative diseases is undoubted. A clinically applicable positron emission tomography (PET) tracer would facilitate the monitoring of disease progression, elucidate the role of muscarinic acetylcholine receptors (mAChR) in disease development and would aid to clarify the diverse natural functions of mAChR regulation throughout the nervous system, which still are largely unresolved. Still, no mAChR PET tracer has yet found broad clinical application, which demands mAChR tracers with improved imaging properties. This paper reviews strategies of mAChR PET tracer design and summarizes the binding properties and preclinical evaluation of recent mAChR tracer candidates. Furthermore, this work identifies the current major challenges in mAChR PET tracer development and provides a perspective on future developments in this area of research.

Keywords: PET; molecular imaging; muscarinic acetylcholine receptors; tracer development.

Figure 1

Graphical illustration of the mAChR M1 crystal structure PDB:5CXV [54] using Mol* [62]. The approximal location of the orthosteric binding site and the allosteric binding sites are highlighted. The receptor structure contains the co-crystallized orthosteric antagonist tiotropium, which is displayed in ‘ball and stick’ style. In the side view the protein is displayed as cartoon and in the top view it is displayed as Gaussian surface.

Figure 2

Structures and binding properties of mAChR ligands previously evaluated in vivo as imaging probes. Emphasis is given on novelties since the previous review in 2006 [5]. First synthesis: (R,S)-[¹²³I]IQNB [100], [carbonyl-¹¹C]QNB [66], [¹¹C]scopolamine [101], [¹¹C]benztropine [102], [¹¹C]TRB [103], [¹¹C]NMPB [104], [¹⁸F]4-FDEX [76], [¹¹C]xanomeline [105], [¹⁸F]FP-TZTP [106], (+)-[¹¹C]3-MPB [107], [¹¹C]GSK1034702 [108], [¹¹C]AF150(S) [92], (S,R)-[¹¹C]1-methylpiperidin-3-yl)2-cyclopentyl-2-hydroxy-2-phenylacetate [94], [¹¹C]LSN3172176 [109], [¹¹C]M₄R-1023 [98], [¹¹C]MK-6884 [99]. First in man/animal: (R,S)-[¹²³I]IQNB [30], [carbonyl-¹¹C]QNB [110], [¹¹C]scopolamine [67], [¹¹C]benztropine [68], [¹¹C]TRB[69], [¹¹C]NMPB [70], [¹⁸F]4-FDEX [78], [¹¹C]xanomeline [86], [¹⁸F]FP-TZTP [83], (+)-[¹¹C]3-MPB [75], [¹¹C]GSK1034702 [88], [¹¹C]AF150(S) [93], (S,R)-[¹¹C]1-methylpiperidin-3-yl)2-cyclopentyl-2-hydroxy-2-phenylacetate [94], [¹¹C]LSN3172176 [96], [¹¹C]M₄R-1023 [98], [¹¹C]MK-6884 [111].

Figure 2

Structures and binding properties of mAChR ligands previously evaluated in vivo as imaging probes. Emphasis is given on novelties since the previous review in 2006 [5]. First synthesis: (R,S)-[¹²³I]IQNB [100], [carbonyl-¹¹C]QNB [66], [¹¹C]scopolamine [101], [¹¹C]benztropine [102], [¹¹C]TRB [103], [¹¹C]NMPB [104], [¹⁸F]4-FDEX [76], [¹¹C]xanomeline [105], [¹⁸F]FP-TZTP [106], (+)-[¹¹C]3-MPB [107], [¹¹C]GSK1034702 [108], [¹¹C]AF150(S) [92], (S,R)-[¹¹C]1-methylpiperidin-3-yl)2-cyclopentyl-2-hydroxy-2-phenylacetate [94], [¹¹C]LSN3172176 [109], [¹¹C]M₄R-1023 [98], [¹¹C]MK-6884 [99]. First in man/animal: (R,S)-[¹²³I]IQNB [30], [carbonyl-¹¹C]QNB [110], [¹¹C]scopolamine [67], [¹¹C]benztropine [68], [¹¹C]TRB[69], [¹¹C]NMPB [70], [¹⁸F]4-FDEX [78], [¹¹C]xanomeline [86], [¹⁸F]FP-TZTP [83], (+)-[¹¹C]3-MPB [75], [¹¹C]GSK1034702 [88], [¹¹C]AF150(S) [93], (S,R)-[¹¹C]1-methylpiperidin-3-yl)2-cyclopentyl-2-hydroxy-2-phenylacetate [94], [¹¹C]LSN3172176 [96], [¹¹C]M₄R-1023 [98], [¹¹C]MK-6884 [111].