Radiosynthesis and evaluation of [¹¹C]BTA-1 and [¹¹C]3'-Me-BTA-1 as potential radiotracers for in vivo imaging of β-amyloid plaques

Summary

Aim: To evaluate the in vitro and in vivo characteristics of [N-methyl-¹¹C]2-(4'-(methylaminophenyl)-benzothiazole ([¹¹C]BTA-1) as well as [N-methyl-¹¹C]2-(3'-methyl- 4'-(methylamino)phenyl)-benzothiazole ([¹¹C]3'-Me- BTA-1) as diagnostic markers of amyloid-β (Aβ) in Alzheimer's disease (AD). Material, methods: Brain uptake and clearance was determined in wild-type mice. Binding affinities (Ki) of [¹¹C]BTA-1 and [¹¹C]3'-Me-BTA-1 for aggregated Aβ(1-40) fibrils were assessed. Autoradiography was performed on brain sections of AD patients. To demonstrate binding specificity in vivo BTA-1 was injected i.p. in transgenic mice (Tg2576). Brain sections were analysed consecutively. Additionally, a [¹¹C]BTA-1 PET study of an AD patient and a healthy control was performed. Results: In mice brain uptake and clearance of [¹¹C]BTA-1 is compatible with the half life of ¹¹C (2 min: 12.7 % ID/g; 30 min: 4.6% ID/g). In contrast clearance rate of [¹¹C]3'-Me- BTA-1 is too slow (2 min 4% ID/g; 30 min 12% ID/g) to achieve sufficient clearance of free and non specifically bound radioactivity. Ki of [¹¹C]BTA-1 is 11 nmol/l and that of [¹¹C]3'-Me-BTA-1 27 nmol/l. Both radioligands label Aβ selectively and specifically in AD patients and transgenic mice in vitro. The in vivo stained brain sections show a labelling of Aβ plaques. The AD patient has a higher prefrontal, parietal and striatal [¹¹C]BTA-1 accumulation than the healthy control. Metabolite analysis revealed approximately 75% intact [¹¹C]BTA-1 after 30min in plasma.[ ¹¹C]BTA-1 is favourable for in vivo imaging of Aβ due to its rapid brain entry, sufficient clearance and good binding affinity for Aβ. Conclusion: The ability to label Aβ plaques in vivo in human subjects supports the suitability of [¹¹C]BTA-1 as a plaque imaging agent.

Zusammenfassung

Das Ziel dieser Studie war die Evaluierung der in vitro und in vivo Eigenschaften von [¹¹C]BTA-1 und [¹¹C]3'-Me-BTA-1 als diagnostische Marker von β-Amyloid-Plaques bei der Demenz vom Alzheimertyp (DAT). Material, Methoden: Die Hirnaufnahme und -auswaschung der Radiopharmaka wurden in Wildtyp-Mausen untersucht. Die Bindungsaffinitat (Ki) von [¹¹C]BTA-1 und [¹¹C]3'-Me-BTA-1 an aggregierte Aβ (1-40)-Fibrillen wurde bestimmt. Eine Autoradiographie wurdeanGehirnschnittenvonDAT- Patientendurchgefuhrt.ZurDarstellung der Bindungsspezifitat in vivo wurde BTA-1 i.p. in transgene Mause injiziert (Tg2576). Nachfolgend wurden Gehirnschnitte analysiert. Zusatzlich wurde eine [¹¹C]BTA-1-PET Untersuchung bei einem DAT-Patienten und einer gesunden Kontrollperson durchgefuhrt. Ergebnisse: Bei Mausen ist die Gehirnaufnahme und Auswaschung von [¹¹C]BTA-1 mit der physikalischen Halbwertszeit von ¹¹C (2 min: 12.7 % ID/g; 30 min: 4.6% ID/g) kompatibel. Im Gegensatz dazu ist die Auswaschung von [¹¹C]3'-Me-BTA-1 zu langsam (2 min 4% ID/g; 30min12%ID/g),umeinausreichendesAuswaschenvonfreier nicht gebundener Radioaktivitat aus dem Gehirn zu gewahrleisten. Der Ki von [¹¹C]BTA-1 wurde zu 11 nmol/l und von [¹¹C]3'-Me-BTA-1 zu 27 nmol/l bestimmt. Beide Radioliganden binden selektiv und spezifisch an Aβ bei Hirnschnitten von DAT-Patienten und transgenen Mausen. Die in vivo markierten Hirnschnitte zeigen ebenfalls eine Bindung von BTA-1 an Aβ- Plaques. Der DAT-Patient wies eine hohere prafrontale, parietale, cingulare und striatale [¹¹C]BTA-1-Akkumulation im Vergleich zur gesunden Kontrollperson auf. Die Plasma-Metabolitenanalyse fur [¹¹C]BTA-1 zeigte etwa 75% intaktes [¹¹C]BTA-1 nach 30 min. Schlussfolgerung: [¹¹C]BTA-1 ist geeignet fur die In-vivo-Darstellung von Aβ-Plaques auf Grund des schnellen Gehirneintritts, der ausreichenden Clearance und der guten Bindungsaffinitat fur Aβ. Insbesondere die Fahigkeit Aβ-Plaques in vivo darzustellen, unterstutzt die Eignung von [¹¹C]BTA-1 fur die bildgebende Diagnostik.

Keywords

Alzheimer's disease - PET - amyloid plaques

Schlüsselwörter

Alzheimer - PET - Amyloid-Plaques

^* contributed equally to the study

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