RT Journal Article
SR Electronic
T1 Novel <sup>18</sup>F-Labeled κ-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of <sup>18</sup>F-LY2459989 in Nonhuman Primates
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 140
OP 146
DO 10.2967/jnumed.117.195586
VO 59
IS 1
A1 Li, Songye
A1 Cai, Zhengxin
A1 Zheng, Ming-Qiang
A1 Holden, Daniel
A1 Naganawa, Mika
A1 Lin, Shu-Fei
A1 Ropchan, Jim
A1 Labaree, David
A1 Kapinos, Michael
A1 Lara-Jaime, Teresa
A1 Navarro, Antonio
A1 Huang, Yiyun
YR 2018
UL http://jnm.snmjournals.org/content/59/1/140.abstract
AB The κ-opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several 11C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of 18F-LY2459989 as the first 18F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11C-LY2459989. Methods: The novel radioligand 18F-LY2459989 was synthesized by 18F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time–activity curves and the calculation of binding parameters. Results: With the iodonium ylide precursor, 18F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (&gt;99%), and mean molar activity (1,175 GBq/μmol; n = 6). In monkeys, 18F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of 18F-LY2459989 in vivo. Regional time–activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex &gt; insula &gt; caudate/putamen &gt; frontal cortex &gt; temporal cortex &gt; thalamus, consistent with the reported KOR distribution in the monkey brain. Conclusion: The evaluation of 18F-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of 18F-LY2459989 and 11C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that 18F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo.