Synthesis and evaluation of N-isopropyl-p-[11C]methylamphetamine as a novel cerebral blood flow tracer for positron emission tomography

EJNMMI Research

Masakatsu Kanazawa¹  Norihiro Harada¹  Takeharu Kakiuchi¹  Hiroyuki Ohba¹  Tetsuro Tago²  Jun Toyohara²  Muneyuki Sakata²  Kiichi Ishiwata³ 

[1] Central Research Laboratory, Hamamatsu Photonics, 5000 Hiraguchi, Hamakita-ku, 434-8601, Hamamatsu, Japan;Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, 173-0015, Tokyo, Japan;Southern TOHOKU Drug Discovery and Cyclotron Research Center, Southern TOHOKU Research Institute for Neuroscience, 7-61-2 Yatsuyamada, 963-8052, Koriyama, Japan;Department of Biofunctional Imaging, Fukushima Medical University, 1 Hikariga-oka, 960-1295, Fukushima, Japan;

关键词: Phenylalkylamine;    Cerebral blood flow;    Positron emission tomography;    Non-human primate;    Carbon-11;   

DOI  :  10.1186/s13550-020-00702-5

来源: Springer

【 摘 要 】

IntroductionIncreases in fasting plasma glucose (PG) levels lead to a decrease in 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) uptake in the normal brain, especially in the precuneus, resulting in an Alzheimer’s disease (AD)-like uptake pattern. Therefore, patients with higher PG levels, such as those with diabetes, can be erroneously diagnosed with AD when positron emission tomography (PET) imaging is done using [18F]FDG, due to reduced uptake of [18F]FDG in the precuneus. To help avoid an erroneous diagnosis of AD due to differences in glucose metabolism, evaluating cerebral blood flow (CBF) in the brain is useful. However, current techniques such as single photon emission computed tomography (SPECT) and [15O]H2O PET have limitations regarding early diagnosis of AD because the images they produce are of low resolution. Here, we developed a novel CBF PET tracer that may be more useful than [18F]FDG for diagnosis of AD.MethodsWe synthesized and evaluated N-isopropyl-p-[11C]methylamphetamine ([11C]4) as a carbon-11-labeled analogue of the standard CBF SPECT tracer N-isopropyl-p-[123I]iodoamphetamine. Fundamental biological evaluations such as biodistribution, peripheral metabolism in mice, and brain kinetics of [11C]4 in non-human primates with PET with successive measurement of [15O]H2O were performed.Results[11C]4 was synthesized by methylation of the corresponding tributyltin precursor (2) with [11C]MeI in a palladium-promoted Stille cross-coupling reaction. The brain uptake of [11C]4 in mice peaked at 5–15 min after injection and then promptly decreased. Most radioactivity in the brain was detected in the unchanged form, although in the periphery, [11C]4 was rapidly metabolized to hydrophilic components. Acetazolamide (AZM) treatment significantly increased the brain uptake of [11C]4 without affecting the blood levels of radioactivity in mice. Preliminary kinetics analysis showed that the K1 of [11C]4 reflected regional CBF in a vehicle-treated monkey, but that the K1 did not reflect CBF in higher flow regions after AZM loading.Conclusion[11C]4 is a potential novel CBF PET tracer. Further validation studies are needed before [11C]4 can be used in humans.

【 授权许可】

CC BY