The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs), ubiquitously distributed in the human brain, are implicated in various neurophysiological processes and in the pathophysiology and/or treatment strategies of Alzheimer's and Parkinson's diseases, Tourette's syndrome, epilepsy, schizophrenia, depression, and anxiety, as well as being particularly affected in tobacco dependence/withdrawal. In the past two decades, researchers have developed an extensive series of radioligands for the assessment of nAChRs in vivo through emission tomography, PET and SPECT. Several radioligands, derivatives of A-85380: 2-[(18)F]FA, 6-[(18)F]FA and 5-[(123)I]IA, are now being employed for the evaluation of nAChR in humans with PET and SPECT. Displaying better imaging properties than (11)C-nicotine and a better toxicity profile than epibatidine analogs, they have allowed quantification of thalamic nAChR in the human brain. Nevertheless, A-85380 derivatives still exhibit slow brain kinetics and a moderate signal-to-noise ratio. Current research efforts on the part of PET/SPECT radiochemists, therefore, have focused on development of new, highly specific and highly selective nAChR radioligands with improved brain kinetics that are able to localize high-affinity nAChRs in vivo. Key examples of new PET/SPECT ligands that are derived from several different structural classes are discussed along with a review of their chemical as well as their in vitro and/or in vivo properties. In particular, new PET nAChR radioligands will be examined that either present faster brain kinetics allowing simple and reliable quantification approaches or higher binding potentials suitable for the evaluation of extrathalamic nAChR.

Identification of embryonic stem cell–derived midbrain dopaminergic neurons for engraftment

“…15 and Supplemental Figure 9, A-D). This gene is interesting given the well-established link between tobacco use and decreased rates of PD and because radiolabeled ligands to this receptor have been used for visualization of the human midbrain by single-photon emission computed tomography (16). Upon further investigation (14), we found that another nAChR subunit, CHRNB3, was also expressed in the FOXA2/LMX1A domain of the developing human ventral midbrain (Supplemental Figure 9E).…”

18F-ZW-104: A New Radioligand for Imaging Neuronal Nicotinic Acetylcholine Receptors—In Vitro Binding Properties and PET Studies in Baboons

“…N-Boc-protected 18 F-ZW-104 was eluted from the cartridge with CH 2 Cl 2 (3 mL) into a 5-mL reaction vial containing trifluoroacetic acid (TFA) (0.1 mL). Elution was repeated twice with 1 mL of CH 2 residue was redissolved in CH 2 Cl 2 (2 mL) and concentrated again to dryness to minimize TFA presence (at 65°C275°C under a gentle nitrogen stream for 2-3 min). Finally, the residue was redissolved in the HPLC solvent used for purification (1.0 mL), and the crude was injected onto HPLC (HPLC method A).…”

“…PET offers the opportunity to monitor changes in human nicotinic acetylcholine receptors (nAChRs) in vivo. However, there are certain difficulties in the development of suitable radioligands for the in vivo imaging of nAChRs (2), one of them being the low density of nAChRs in extrathalamic areas. Therefore, there is a need for radioligands with high affinities (probably less than 1 nM) and radiosyntheses yielding high specific radioactivities.…”

“…The role of lipophilicity of the radioligand remains a subject of debate, but a relationship exists between the lipophilicity and nondisplaceable binding. Research efforts from radiochemists have focused on the development of highly specific radioligands with improved brain kinetics (2). A new emerging, promising field is the use of antagonists at nAChRs (3,4), but these compounds need more experiments to confirm their preliminary attractive characteristics.…”

PET Imaging of High-Affinity α4β2 Nicotinic Acetylcholine Receptors in Humans with 18F-AZAN, a Radioligand with Optimal Brain Kinetics

“…Available radioligands for the quantitative PET imaging of nAChR in humans, 2-18 F-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-18 F-FA) (7) and 6-18 F-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (6-18 F-FA), exhibit slow distribution kinetics in primates, requiring hours of scanning (3,(8)(9)(10)(11)(12)(13)(14)(15). Even the bolusplus-infusion approach, which allows a shorter scanning time, does not resolve the problem completely because of the long postinjection waiting period of more than 6 h (16).…”