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J Nucl Med. 2008; 49 (Supplement 1):130P
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Neurosciences: Basic Science

Emerging Ligands and Targets

[18F]JHU87522, a PET radioligand for cerebral nicotinic acetylcholine receptor with rapid brain kinetics, high binding potentials and good safety profile

Yongjun Gao1, Hiroto Kuwabara1, Charles Spivak2, Hayden Ravert1, Anil Kumar1, Mohab Alexander1, Dean Wong1, Robert Dannals1 and Andrew Horti1

1 Radiology, Johns Hopkins Medicine, Baltimore, Maryland; 2 NIDA, NIH, Baltimore, Maryland

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Objectives: The currently available radioligands for PET imaging of nAChR in humans, 2-[18F]FA and 6-[18F]FA, exhibit slow brain kinetics. As the result, PET studies with these radioligands are logistically impractical for many imaging centers. Here we introduce [18F]JHU87522 (JHU), a novel, high affinity nAChR PET radioligand with rapid brain kinetics and high binding potentials (see synthesis in Gao et al., this meeting.

Methods: Regional brain distribution, blockade, metabolism and toxicology of JHU have been done in mice and baboon. A functional assay was performed at the SH-EP1 cells stably expressing human {alpha}4β2-nAChR.

Results: Rapid and high uptake of radioactivity in the baboon brain regions (peak in the thalamus (Th) is at 7-30 min, 600%SUV) with robust washout thereafter was seen after the bolus injection of JHU. The regional brain distribution of radioactivity was similar to those of 2-[18F]FA and 6-[18F]FA. PET modeling demonstrated that only 90 min of scanning was needed for accurate determination of the binding potential values (BPTh=4.8) versus 6-7 h for [18F]FA (BPTh=2). In the baboon blockade study with cytisine (2 mg/kg, s.c.) there was a 93% reduction of radioactivity in Th, the region with high density of nAChR. The toxicology study in mice showed that JHU exhibits lower toxicity than 2-FA. The functional assay proved that JHU is an antagonist for {alpha}4β2-nAChR.

Conclusions: JHU exhibits rapid brain kinetic, high binding potentials and brain uptake and a good safety profile. It holds promise as a superior substitute of 2-[18F]FA and 6-[18F]FA for studying nAChR in the human brain by PET.

Research Support: JHU Radiology, NIH grant R21MH079017





This Article
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Right arrow Articles by Horti, A.
PubMed
Right arrow Articles by Gao, Y.
Right arrow Articles by Horti, A.