Development and preclinical evaluation of radioligands for the PET studies of cerebral adenosine A1 and A2A receptors

Shivashankar Shivashankar

Development and preclinical evaluation of radioligands for the PET studies of cerebral adenosine A1 and A2A receptors

Vertaalde titel van de bijdrage: Ontwikkeling en preklinische evaluatie van radioliganden voor PET-studies van adenosine A1 en A2a receptoren in het brein

Shivashankar Shivashankar

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Vanwege het klinisch belang van adenosine A1 en A2A receptoren (A1Rs, A2ARs) is er een sterke behoefte aan het ontwikkelen van radioliganden met hoge affiniteit en subtype-selectiviteit ten einde de dichtheid van deze receptoren met PET in kaart te kunnen brengen. Het hoofddoel van dit proefschrift is de ontwikkeling van radioliganden met een hoge mate van selectiviteit, een affiniteit die hoog genoeg is om A2ARs te kunnen afbeelden maar niet zó hoog dat vaststelling van het aantal receptoren bemoeilijkt wordt. Er is gekeken naar goede farmacokinetische eigenschappen en een grotere signaal-ruisverhouding dan de bestaande radioliganden zoals [11C]SCH442416.

Een retrosynthetische benadering werd toegepast voor de bereiding van niet-radioactieve fluoranaloga van SCH442416 en O-desmethyl preladenant. [18F]Fluoropropyl SCH442416 {[18F]FPSCH) en [11C]preladenant werden ontwikkeld als nieuwe liganden voor het afbeelden van A2ARs in de hersenen met behulp van PET. Liganden die met fluor-18 zijn gemerkt bieden logistieke voordelen boven 11C-radioliganden, en kunnen naar verafgelegen centra worden vervoerd die niet over een kostbaar on-site cyclotron beschikken. Bovengenoemde radioliganden konden worden gemaakt met hoge specifieke radioactiviteit en radiochemische zuiverheid. De verdeling van de radioliganden werd onderzocht met behulp van PET, ex vivo biodistributie en in vitro autoradiografie. De regionale verdeling van [18F]FPSCH en [11C]preladenant kwam overeen met de bekende verdeling van A2ARs in de hersenen van de rat, met de hoogste opname in het striatum. PET toonde aan dat [18F]FPSCH en [11C]preladenant een gunstige farmacokinetiek bezitten in de hersenen. De eigenschappen van beide tracers maken hen geschikt voor het afbeelden van A2A receptoren.

Vertaalde titel van de bijdrage	Ontwikkeling en preklinische evaluatie van radioliganden voor PET-studies van adenosine A1 en A2a receptoren in het brein
Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Elsinga, Philip, Supervisor Dierckx, Rudi, Supervisor van Waarde, Aren, Co-supervisor
Datum van toekenning	15-sep.-2014
Plaats van publicatie	[S.l.]
Uitgever	[S.n.]
Gedrukte ISBN's	978-90-367-7226-6
Elektronische ISBN's	978-90-367-7225-9
Status	Published - 2014

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title = "Development and preclinical evaluation of radioligands for the PET studies of cerebral adenosine A1 and A2A receptors",

abstract = "Because of the clinical importance of A1Rs and A2ARs, the development of high affinity and subtype-selective radioligands for mapping AR density is urgently needed. The main objective of this thesis is to develop A2AR tracers with a high degree of selectivity, sufficient affinity to image receptors but not so high as to compromise receptor quantification, good pharmacokinetic properties, and larger target-to-nontarget ratios than existing radiotracers such as [11C]SCH442416. A retrosynthetic approach was adopted for the synthesis of nonradioactive fluorinated SCH442416 analogues and O-desmethyl preladenant. [18F]Fluoropropyl SCH442416 ([18F]FPSCH) and [11C]Preladenant were developed as new PET ligands for mapping cerebral adenosine A2A receptors (A2ARs). Fluorinated ligands can provide logistic advantages over C-11 labeled tracers, and be distributed to remote centers without an expensive on-site cyclotron. The two tracers mentioned above were synthesized in high specific activity and purity. Tracer tissue distribution was studied by PET, ex-vivo analysis and in vitro autoradiography. The regional uptake of [18F]FPSCH and [11C]preladenant was consistent with known A2ARs distribution in the rat brain, with highest uptake in striatum. PET showed that [18F]FPSCH and [11C]preladenant have favorable cerebral kinetics. Both tracers exhibit suitable characteristics for PET imaging of A2ARs.",

author = "Shivashankar Shivashankar",

year = "2014",

language = "English",

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publisher = "[S.n.]",

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T1 - Development and preclinical evaluation of radioligands for the PET studies of cerebral adenosine A1 and A2A receptors

AU - Shivashankar, Shivashankar

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N2 - Because of the clinical importance of A1Rs and A2ARs, the development of high affinity and subtype-selective radioligands for mapping AR density is urgently needed. The main objective of this thesis is to develop A2AR tracers with a high degree of selectivity, sufficient affinity to image receptors but not so high as to compromise receptor quantification, good pharmacokinetic properties, and larger target-to-nontarget ratios than existing radiotracers such as [11C]SCH442416. A retrosynthetic approach was adopted for the synthesis of nonradioactive fluorinated SCH442416 analogues and O-desmethyl preladenant. [18F]Fluoropropyl SCH442416 ([18F]FPSCH) and [11C]Preladenant were developed as new PET ligands for mapping cerebral adenosine A2A receptors (A2ARs). Fluorinated ligands can provide logistic advantages over C-11 labeled tracers, and be distributed to remote centers without an expensive on-site cyclotron. The two tracers mentioned above were synthesized in high specific activity and purity. Tracer tissue distribution was studied by PET, ex-vivo analysis and in vitro autoradiography. The regional uptake of [18F]FPSCH and [11C]preladenant was consistent with known A2ARs distribution in the rat brain, with highest uptake in striatum. PET showed that [18F]FPSCH and [11C]preladenant have favorable cerebral kinetics. Both tracers exhibit suitable characteristics for PET imaging of A2ARs.

AB - Because of the clinical importance of A1Rs and A2ARs, the development of high affinity and subtype-selective radioligands for mapping AR density is urgently needed. The main objective of this thesis is to develop A2AR tracers with a high degree of selectivity, sufficient affinity to image receptors but not so high as to compromise receptor quantification, good pharmacokinetic properties, and larger target-to-nontarget ratios than existing radiotracers such as [11C]SCH442416. A retrosynthetic approach was adopted for the synthesis of nonradioactive fluorinated SCH442416 analogues and O-desmethyl preladenant. [18F]Fluoropropyl SCH442416 ([18F]FPSCH) and [11C]Preladenant were developed as new PET ligands for mapping cerebral adenosine A2A receptors (A2ARs). Fluorinated ligands can provide logistic advantages over C-11 labeled tracers, and be distributed to remote centers without an expensive on-site cyclotron. The two tracers mentioned above were synthesized in high specific activity and purity. Tracer tissue distribution was studied by PET, ex-vivo analysis and in vitro autoradiography. The regional uptake of [18F]FPSCH and [11C]preladenant was consistent with known A2ARs distribution in the rat brain, with highest uptake in striatum. PET showed that [18F]FPSCH and [11C]preladenant have favorable cerebral kinetics. Both tracers exhibit suitable characteristics for PET imaging of A2ARs.

M3 - Thesis fully internal (DIV)

SN - 978-90-367-7226-6

PB - [S.n.]

CY - [S.l.]

ER -

Development and preclinical evaluation of radioligands for the PET studies of cerebral adenosine A1 and A2A receptors

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