# PET imaging of a4b2 nicotinic receptor upregulation and smoking cessation

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $691,354

## Abstract

Abstract
Tobacco continues to be widely used world-wide, primarily via cigarette smoking, and is the leading cause of
preventable deaths in the United States. Tobacco use is driven by nicotine addiction, which starts by nicotine
binding to high-affinity nicotine binding sites in brain. 80-90% of the high-affinity sites are located on α4β2-type
nicotinic acetylcholine receptors (α4β2Rs). Prolonged nicotine exposure increases high-affinity α4β22R binding
sites in brain, a process termed “upregulation”, linked to craving and withdrawal in nicotine addiction. This
proposal is based on our recent discovery that α4β2R ligands that are weak bases, such as the smoking
cessation reagent varenicline (Chantix), can be selectively trapped in α4β2R-containing acidic vesicles of cells
and neurons. Slow release of trapped varenicline reduces the effects of nicotine upregulation. Selective
trapping is further regulated by nicotine upregulation, which increases the numbers of α4β2R-containing acidic
vesicles. Nicotine, also a weak base, is not trapped because its ligand pKa and affinity for α4β22Rs is lower
than that of varenicline. These results provide a new paradigm for how varenicline causes smoking cessation.
They also provide new information about the potential cellular distribution of α4β22R PET probes, all of which
are weak bases. Like varenicline and nicotine, different α4β2R PET probes have different ligand pKas and
affinities for α4β2Rs, which explains differences in kinetics, displaceable binding by varenicline and nicotine,
non-displaceable binding and metabolism.
While a number of studies have used PET probes specific for α4β22R high-affinity binding sites in brain, these
studies are complicated by the interpretations of the binding and binding kinetics especially when nicotine
and/or varenicline are present. Using our concept about the trapping of α4β2R weak base ligands in
intracellular acidic vesicles, we will develop new cellular and whole models of PET probe kinetics that take into
account α4β2R ligand trapping in acidic vesicles. There is the potential of wider application of the PET
methods that will be developed in this application, since for α4β2R PET imaging is currently underway in a
number of brain disorders. The goals of this proposal are to examine how our discovery of the trapping of weak
base α4β2R ligands in acid vesicles affects the imaging of α4β2Rs using PET probes and to use PET probe
imaging to examine how nicotine causes α4β2R upregulation and how varenicline alters upregulation.

## Key facts

- **NIH application ID:** 9919536
- **Project number:** 5R01DA044760-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Chin-Tu Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $691,354
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9919536

## Citation

> US National Institutes of Health, RePORTER application 9919536, PET imaging of a4b2 nicotinic receptor upregulation and smoking cessation (5R01DA044760-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9919536. Licensed CC0.

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