¹⁸F-labelled CCR1-receptor antagonist is not suitable for imaging of Alzheimer's disease

Summary

Diagnosis of Alzheimer’s disease (AD) with positron emission tomography (PET) using ¹⁸F-fluorodeoxyglucose (FDG) relies on typical alterations of brain glucose metabolism which are, however, not disease specific. Amyloid- β imaging has not entered clinical routine yet. Post mortem histological specimen of brain tissue from AD patients revealed enhanced expression of the chemotactic cytocine receptor 1 (CCR1). Participants, methods: CCR1-antagonist ZK811460 was labeled with fluorine-18 to explore its possible use as specific diagnostic tool in AD. Tracer characterization comprising PET imaging of brain and metabolite analysis was performed in AD patients and controls. Results: Neither qualitative evaluation nor quantitative compartment analysis of PET data did show any enhanced binding of the ¹⁸F-labeled CCR1-antagonist in the brain of AD patients or controls. Conclusion: ¹⁸F-ZK811460 did not fulfill the expectation as diagnostic tracer in PET imaging of AD.

Zusammenfassung

Die Diagnostik der Demenz vom Alzheimertyp (AD) mit Positronenemissionstomographie (PET) und dem Glukoseanalogon ¹⁸F-Fluor-des oxyglukose (FDG) beruht auf einer typischen, aber nicht krankheitsspezifischen Veränderung im zerebralen Glukosestoffwechsel. PET mit Amyloid-β-affinen Tracern steht nicht für die klinische Routine zur Verfügung. Postmortem- Untersuchungen an histologischen Hirnschnitten von AD-Patienten zeigten eine erhöhte Expression des chemotaktischen Zytokinrezeptors 1 (CCR1). Ziele, Teilnehmer, Methoden: Der CCR1-Antagonist ZK811460 wurde mit Fluor-18 markiert, um seine Eigenschaften als ein spezifisches Diagnostikum für AD zu untersuchen. Die Charakterisierung des Radiotracers beinhaltete PET-Untersuchungen des Gehirns und Metabolitenanalyse bei AD-Patienten und gesunden Normalpersonen. Ergebnisse: Weder in der qualitativen Bildauswertung noch in der quantitativen Kompartmentanalyse der PET-Daten zeigte sich eine erhöhte Bindung des ¹⁸F-markierten CCR1-Antagonisten im Gehirn der AD-Patienten oder der Normalpersonen. Schlussfolgerung: ¹⁸F-ZK811460 erfüllte nicht die Erwartungen als PET-Diagnostikum bei Alzheimer- Demenz.

Keywords

Alzheimer’s disease - CCR1 receptor antagonist - positron emission tomography

Schlüsselwörter

Demenz vom Alzheimertyp - CCR1-Rezeptor- Antagonist - Positronenemissionstomo graphie

• References

• 1 Barthel H, Gertz HJ, Dresel S. et al. Cerebral amyloid-beta PET with florbetaben (¹⁸F) in patients with Alzheimer's disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol 2011; 10: 424-435.
• 2 Clark CM, Schneider JA, Bedell BJ. et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 2011; 305: 275-283.
• 3 Delis D, JH K, Kaplan E, Ober B.. California Verbal Learning Test: Adult version manual. The Psychological Corporation.. San Antonio: 1987
• 4 Folstein M, Folstein S, McHugh P. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189-198.
• 5 Halks-Miller M, Schroeder ML, Haroutunian V. et al. CCR1 is an early and specific marker of Alzheimer's disease. Ann Neurol 2003; 54: 638-646.
• 6 Herholz K, Salmon E, Perani D. et al. Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET. Neuroimage 2002; 17: 302-316.
• 7 Hoffman JM, Hanson MW, Welsh KA. et al. Interpretation variability of ¹⁸FDG-positron emission tomography studies in dementia. Invest Radiol 1996; 31: 316-322.
• 8 Kepe V, Barrio JR, Huang SC. et al. Serotonin 1A receptors in the living brain of Alzheimer's disease patients. Proc Natl Acad Sci USA 2006; 103: 702-707.
• 9 Huber W, Poeck D, Weniger D, Willmes K.. Aachener Aphasie Test - Handanweisungen.. Göttingen: Hogrefe; 1983
• 10 Klunk WE, Engler H, Nordberg A. et al. Imaging the pathology of Alzheimer's disease: amyloid-imaging with positron emission tomography. Neuroimaging Clin N Am 2003; 13: 781-789.
• 11 Liang M, Mallari C, Rosser M. et al. Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J Biol Chem 2000; 275: 19000-19008.
• 12 Mäding P, Füchtner F, Johannsen B. et al. ¹⁸F-Labelling of a potent nonpeptide CCR1 antagonist: Synthesis of 1-(5-chloro-2-{2-[(2R)-4-(4-[¹⁸F]fluorobenzyl)-2-methylpiperazin-1-yl] 2-oxoethoxy}phenyl)urea in an automated module. J Label Compd Radiopharm 2006; 49: 253-262.
• 13 Ng S, Villemagne VL, Berlangieri S. et al. Visual assessment versus quantitative assessment of ¹¹C-PIB PET and ¹⁸F-FDG PET for detection of Alzheimer's disease. J Nucl Med 2007; 48: 547-552.
• 14 Patlak C, Blasberg R, Fenstermacher J. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 1983; 3: 1-7.
• 15 Rowe CC, Ackerman U, Browne W. et al. Imaging of amyloid beta in Alzheimer's disease with ¹⁸F-BAY94–9172, a novel PET tracer: proof of mechanism. Lancet Neurol 2008; 7: 129-135.
• 16 Spreen O, Strauss E.. A compendium of neuropsychological tests.. New York: Oxford University Press; 1998
• 17 Van den Hoff J. Principles of quantitative positron emission tomography. Amino Acids 2005; 29: 341-353.