Nicotinic α4β2 receptor imaging agents: Part II. Synthesis and biological evaluation of 2-[18F]fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (18F-nifene) in rodents and imaging by PET in nonhuman primate

Pichika, Rama; Easwaramoorthy, Balasubramaniam; Collins, Daphne; Christian, Bradley T.; Shi, Bingzhi; Narayanan, Tanjore K.; Potkin, Steven G.; Mukherjee, Jogeshwar

doi:10.1016/j.nucmedbio.2005.12.017

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 3 , Pages 295-304, April 2006

Nicotinic α4β2 receptor imaging agents:

Part II. Synthesis and biological evaluation of 2-[¹⁸F]fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (¹⁸F-nifene) in rodents and imaging by PET in nonhuman primate

Presented in part at the 52nd Annual Society of Nuclear Medicine Meeting, Toronto, Canada, June 18–23, 2005.

Rama Pichika
- Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-3960, USA
Balasubramaniam Easwaramoorthy
- Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-3960, USA
Daphne Collins
- Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-3960, USA
Bradley T. Christian
- Department of Nuclear Medicine, Kettering Medical Center, Dayton, OH 45429, USA
Bingzhi Shi
- Department of Nuclear Medicine, Kettering Medical Center, Dayton, OH 45429, USA
Tanjore K. Narayanan
- Department of Nuclear Medicine, Kettering Medical Center, Dayton, OH 45429, USA
Steven G. Potkin
- Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-3960, USA
Jogeshwar Mukherjee
- Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-3960, USA
- Corresponding author. Tel.: +1 949 824 2018; fax: +1 949 824 4144.

Received 18 December 2005; received in revised form 21 December 2005; accepted 29 December 2005.

Abstract

The α4β2 nicotinic acetylcholine receptor (nAChR) has been implicated in various neurodegenerative diseases. Optimal positron emission tomography (PET) imaging agents are therefore highly desired for this receptor. We report here the development and initial evaluation of 2-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (nifene). In vitro binding affinity of nifene in rat brain homogenate using ³H-cytisine exhibited a K_i=0.50 nM for the α4β2 sites. The radiosynthesis of 2-¹⁸F-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (¹⁸F-nifene) was accomplished in 2.5 h with an overall radiochemical yield of 40–50%, decay corrected. The specific activity was estimated to be approx. 37–185 GBq/μmol. In vitro autoradiography in rat brain slices indicated selective binding of ¹⁸F-nifene to anteroventral thalamic (AVT) nucleus, thalamus, subiculum, striata, cortex and other regions consistent with α4β2 receptor distribution. Rat cerebellum showed some binding, whereas regions in the hippocampus had the lowest binding. The highest ratio of >13 between AVT and cerebellum was measured for ¹⁸F-nifene in rat brain slices. The specific binding was reduced (>95%) by 300 μM nicotine in these brain regions. Positron emission tomography imaging study of ¹⁸F-nifene (130 MBq) in anesthetized rhesus monkey was carried out using an ECAT EXACT HR+ scanner. PET study showed selective maximal uptake in the regions of the anterior medial thalamus, ventro-lateral thalamus, lateral geniculate, cingulate gyrus, temporal cortex including the subiculum. The cerebellum in the monkeys showed lower binding than the other regions. Thalamus-to-cerebellum ratio peaked at 30–35 min postinjection to a value of 2.2 and subsequently reduced. The faster binding profile of ¹⁸F-nifene indicates promise as a PET imaging agent and thus needs further evaluation.

Keywords: α4β2 Nicotinic receptors, PET imaging, Autoradiography, Fluorine-18, Nifene