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

Simone M. Crivelli, Andreas Paulus, Jozef Markus, Matthias Bauwens, Dusan Berkes, Helga E. De Vries, Monique T. Mulder, Jochen Walter, Felix M. Mottaghy, Mario Losen, Pilar Martinez-Martinez

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)783-794
Number of pages12
JournalJournal of Alzheimer's Disease
Volume60
Issue number3
DOIs
Publication statusPublished - 2017

Cite this

Crivelli, Simone M. ; Paulus, Andreas ; Markus, Jozef ; Bauwens, Matthias ; Berkes, Dusan ; De Vries, Helga E. ; Mulder, Monique T. ; Walter, Jochen ; Mottaghy, Felix M. ; Losen, Mario ; Martinez-Martinez, Pilar. / Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications. In: Journal of Alzheimer's Disease. 2017 ; Vol. 60, No. 3. pp. 783-794.
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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 = "Alzheimers disease, ceramide, ceramide transporter protein CERT, HPA-12",
author = "Crivelli, {Simone M.} and Andreas Paulus and Jozef Markus and Matthias Bauwens and Dusan Berkes and {De Vries}, {Helga E.} and Mulder, {Monique T.} and Jochen Walter and Mottaghy, {Felix M.} and Mario Losen and Pilar Martinez-Martinez",
year = "2017",
doi = "10.3233/JAD-161231",
language = "English",
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journal = "Journal of Alzheimer's Disease",
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Crivelli, SM, Paulus, A, Markus, J, Bauwens, M, Berkes, D, De Vries, HE, Mulder, MT, Walter, J, Mottaghy, FM, Losen, M & Martinez-Martinez, P 2017, 'Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications' Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 783-794. https://doi.org/10.3233/JAD-161231

Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications. / Crivelli, Simone M.; Paulus, Andreas; Markus, Jozef; Bauwens, Matthias; Berkes, Dusan; De Vries, Helga E.; Mulder, Monique T.; Walter, Jochen; Mottaghy, Felix M.; Losen, Mario; Martinez-Martinez, Pilar.

In: Journal of Alzheimer's Disease, Vol. 60, No. 3, 2017, p. 783-794.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications

AU - Crivelli, Simone M.

AU - Paulus, Andreas

AU - Markus, Jozef

AU - Bauwens, Matthias

AU - Berkes, Dusan

AU - De Vries, Helga E.

AU - Mulder, Monique T.

AU - Walter, Jochen

AU - Mottaghy, Felix M.

AU - Losen, Mario

AU - Martinez-Martinez, Pilar

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Alzheimers disease

KW - ceramide

KW - ceramide transporter protein CERT

KW - HPA-12

UR - http://www.scopus.com/inward/record.url?scp=85030637101&partnerID=8YFLogxK

U2 - 10.3233/JAD-161231

DO - 10.3233/JAD-161231

M3 - Article

VL - 60

SP - 783

EP - 794

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 3

ER -