Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications

Issue title: Mini-Forum on Sphingolipids in Alzheimer’s Disease and Related Disorders

Guest editors: Michelle Mielke and Pilar Martinez

Article type: Research Article

Authors: Crivelli, Simone M.^{a; 1} | Paulus, Andreas^{b; c; d; 1} | Markus, Jozef^e | Bauwens, Matthias^b | Berkes, Dusan^e | De Vries, Helga E.^f | Mulder, Monique T.^g | Walter, Jochen^h | Mottaghy, Felix M.^{b; c; d} | Losen, Mario^a | Martinez-Martinez, Pilar^{a; *}

Affiliations: [a] Maastricht University, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht, The Netherlands | [b] NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands | [c] Department of Medical Imaging, Division of Nuclear Medicine, MUMC, Maastricht, The Netherlands | [d] Division of Nuclear Medicine, Uniklinikum Aachen, Aachen, Germany | [e] Department of Organic Chemistry, Slovak University of Technology, Bratislava, SlovakRepublic | [f] Department of Molecular Cell Biologyand Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands | [g] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands | [h] Department of Neurology, University of Bonn, Bonn, Germany

Correspondence: [*] Correspondence to: Dr. Pilar Martinez-Martinez, Department of Psychiatry and Neuropsychology, Maastricht University, Universiteitssingel 50, 6229ER Maastricht, The Netherlands. Tel.: +31 433881042; E-mail: p.martinez@maastrichtuniversity.nl.

Note: [1] These authors contributed equally to this work.

Abstract: Ceramide levels are increased in blood and brain tissue of Alzheimer’s disease (AD) patients. Since the ceramide transporter protein (CERT) is the only known protein able to mediate non-vesicular transfer of ceramide between organelle membranes, the modulation of CERT function may impact on ceramide accumulation. The competitive CERT inhibitor N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide (HPA-12) interferes with ceramide trafficking. To understand the role of ceramide/CERT in AD, HPA-12 can be a useful tool to modulate ceramide trafficking. Here we first report the synthesis and in vitro properties of HPA-12 radiolabeled with fluorine-18 and present preliminary in vitro and in vivo positron emission tomography (PET) imaging and biodistribution data. In vitro results demonstrated that the fluorination did not alter the biological properties of HPA-12 since the [fluorine-19]HPA-12, interferes with 5-DMB-ceramide trafficking in HeLa cells. Radiolabeled HPA-12, [fluorine-18]HPA-12, was obtained with a radiochemical yield of 90% and a specific activity of 73 MBq/μmol. PET imaging on wild-type mice showed hepatobiliary clearance and a brain uptake on the order of 0.3 standard uptake value (SUV) one hour post injection. Furthermore, the biodistribution data showed that after removal of the blood by intracardial perfusion, radioactivity was still measurable in the brain demonstrating that the [fluorine-18]HPA-12 crosses the blood brain barrier and is retained in the brain.

Keywords: Alzheimer’s disease, ceramide, ceramide transporter protein CERT, HPA-12

DOI: 10.3233/JAD-161231

Journal: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 783-794, 2017