Automatisation and First Evaluation of [18F]FE@SUPPY:2, an Alternative PET-Tracer for the Adenosine A3 Receptor: A Comparison with [18F]FE@SUPPY

Mitterhauser, Markus; Haeusler, Daniela; Mien, Leonhard‐Key; Ungersboeck, Johanna; Nics, Lukas; Lanzenberger, Rupert; Sindelar, Karoline; Viernstein, Helmut; Dudczak, Robert; Kletter, Kurt; Spreitzer, Helmut; Wadsak, Wolfgang

doi:10.2174/1876388x00901010015

Cited by 8 publications

(8 citation statements)

References 26 publications

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“…Therefore, we developed [ 18 F]FE@SUPPY as the first PET tracer for A3R. Radiopreparation and first preclinical evaluation including biodistribution, in vitro metabolic stability studies, ex vivo metabolism studies and in vitro autoradiography [ 2 , 3 , 6 , 12 , 13 ] showed quite promising results. This led us to the next step of the in vivo evaluation of [ 18 F]FE@SUPPY under different conditions (baseline, specific blocking of A3R, blocking of P-gp, mice inoculated with human A3R cell xenografts) using small-animal PET and to assess in vitro tracer stability in human and rat plasma (an overview of the results of this evaluation of [ 18 F]FE@SUPPY as a potential A3R PET tracer is presented in Table 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…The high degree of accumulation of [ 18 F]FE@SUPPY in fat-rich regions might be explained by the high HPLC logD 7.4 of 4.04 [ 6 ]. Surprisingly, baseline conditions in the brain found in this small-animal PET study did not reflect the increasing uptake of the tracer in brain, which we expected on the basis of a previous biodistribution study, in which we found that brain-to-blood ratios increase over time [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

“…Meanwhile, a second potential PET radiotracer has been presented, radiolabelled with 76 Br [ 4 ]. Furthermore, we converted the fluoroethyl ester [ 18 F]FE@SUPPY into the fluoroethyl thioester [ 18 F]FE@SUPPY:2 (5-ethyl 2,4-diethyl-3-((2-[ 18 F]fluoroethyl)-sulfanylcarbonyl)-6-phenylpyridine-5-carboxylate), to serve as a second potential A3R PET tracer [ 5 , 6 ]. Recently, a series of 11 C-labelled 1,2,4-triazolo[4,3-α]quinoxalin-1-one derivatives were synthesized as candidate PET radioligands for A3R [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…The ex vivo biodistribution follows mainly the mRNA pattern of A3 described previously [ 3 ], except for the lack of pronounced tracer uptake in rat testes [ 11 ]. Ex vivo metabolite studies in rats have shown metabolites to a certain extent in the blood [ 12 ], and logP assessment has shown high lipophilicity of the title compound [ 6 ]. Autoradiographic in vitro competition experiments on human and rat brain tissues with [ 125 I]AB-MECA have confirmed the comparability of the title compound FE@SUPPY and the commercially available and highly selective A3 antagonist MRS1523 [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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[18F]FE@SUPPY: a suitable PET tracer for the adenosine A3 receptor? An in vivo study in rodents

Haeusler

Kuntner

Nics

et al. 2015

Eur J Nucl Med Mol Imaging

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PurposeThe adenosine A3 receptor (A3R) is involved in cardiovascular, neurological and tumour-related pathologies and serves as an exceptional pharmaceutical target in the clinical setting. A3R antagonists are considered antiinflammatory, antiallergic and anticancer agents, and to have potential for the treatment of asthma, COPD, glaucoma and stroke. Hence, an appropriate A3R PET tracer would be highly beneficial for the diagnosis and therapy monitoring of these diseases. Therefore, in this preclinical in vivo study we evaluated the potential as a PET tracer of the A3R antagonist [18F]FE@SUPPY.MethodsRats were injected with [18F]FE@SUPPY for baseline scans and blocking scans (A3R with MRS1523 or FE@SUPPY, P-gp with tariquidar; three animals each). Additionally, metabolism was studied in plasma and brain. In a preliminary experiment in a mouse xenograft model (mice injected with cells expressing the human A3R; three animals), the animals received [18F]FE@SUPPY and [18F]FDG. Dynamic PET imaging was performed (60 min in rats, 90 min in xenografted mice). In vitro stability of [18F]FE@SUPPY in human and rat plasma was also evaluated.Results[18F]FE@SUPPY showed high uptake in fat-rich regions and low uptake in the brain. Pretreatment with MRS1523 led to a decrease in [18F]FE@SUPPY uptake (p = 0.03), and pretreatment with the P-gp inhibitor tariquidar led to a 1.24-fold increase in [18F]FE@SUPPY uptake (p = 0.09) in rat brain. There was no significant difference in metabolites in plasma and brain in the treatment groups. However, plasma concentrations of [18F]FE@SUPPY were reduced to levels similar to those in rat brain after blocking. In contrast to [18F]FDG uptake (p = 0.12), the xenograft model showed significantly increased uptake of [18F]FE@SUPPY in the tissue masses from CHO cells expressing the human A3R (p = 0.03). [18F]FE@SUPPY was stable in human plasma.ConclusionSelective and significant tracer uptake of [18F]FE@SUPPY was found in xenografted mice injected with cells expressing human A3R. This finding supports the strategy of evaluating [18F]FE@SUPPY in “humanized animal models”. In conclusion, preclinical evaluation points to the suitability of [18F]FE@SUPPY as an A3R PET tracer in humans.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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[18F]FE@SUPPY: a suitable PET tracer for the adenosine A3 receptor? An in vivo study in rodents

Haeusler

Kuntner

Nics

et al. 2015

Eur J Nucl Med Mol Imaging

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“…Hence, we developed and introduced [ 18 F]FE@SUPPY as the first PET tracer targeting A3R [ 10 , 11 ]. In the meantime, other potential PET tracers including a 76 Br-labelled compound [ 12 ], [ 18 F]FE@SUPPY:2 [ 13 , 14 ] and recently, 11 C-labelled 1,2,4-triazolo[4,3-α]quinoxalin-1-one derivatives [ 15 ] have been synthesized and their affinity for A3R evaluated. So far, in successful preclinical evaluations, [ 18 F]FE@SUPPY [ 14 , 16 , 17 ] has shown an elevated brain to blood ratio in rats [ 11 ], and metabolic stability in vitro and ex vivo in the brain for 30 min [ 16 ], indicating that [ 18 F]FE@SUPPY could potentially be useful for PET imaging studies in humans.…”

Section: Introductionmentioning

confidence: 99%

Hide and seek: a comparative autoradiographic in vitro investigation of the adenosine A3 receptor

Haeusler

Grassinger

Fuchshuber

et al. 2015

Eur J Nucl Med Mol Imaging

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PurposeSince the adenosine A3 receptor (A3R) is considered to be of high clinical importance in the diagnosis and treatment of ischaemic conditions (heart and brain), glaucoma, asthma, arthritis, cancer and inflammation, a suitable and selective A3R PET tracer such as [18F]FE@SUPPY would be of high clinical value for clinicians as well as patients. A3R was discovered in the late 1990s, but there is still little known regarding its distribution in the CNS and periphery. Hence, in autoradiographic experiments the distribution of A3R in human brain and rat tissues was investigated and the specific binding of the A3R antagonist FE@SUPPY and MRS1523 compared. Immunohistochemical staining (IHC) experiments were also performed to validate the autoradiographic findings.MethodsFor autoradiographic competition experiments human post-mortem brain and rat tissues were incubated with [125I]AB-MECA and highly selective compounds to block the other adenosine receptor subtypes. Additionally, IHC was performed with an A3 antibody.ResultsSpecific A3R binding of MRS1523 and FE@SUPPY was found in all rat peripheral tissues examined with the highest amounts in the spleen (44.0 % and 46.4 %), lung (44.5 % and 45.0 %), heart (39.9 % and 42.9 %) and testes (27.4 % and 29.5 %, respectively). Low amounts of A3R were found in rat brain tissues (5.9 % and 5.6 %, respectively) and human brain tissues (thalamus 8.0 % and 9.1 %, putamen 7.8 % and 8.2 %, cerebellum 6.0 % and 7.8 %, hippocampus 5.7 % and 5.6 %, caudate nucleus 4.9 % and 6.4 %, cortex 4.9 % and 6.3 %, respectively). The outcome of the A3 antibody staining experiments complemented the results of the autoradiographic experiments.ConclusionThe presence of A3R protein was verified in central and peripheral tissues by autoradiography and IHC. The specificity and selectivity of FE@SUPPY was confirmed by direct comparison with MRS1523, providing further evidence that [18F]FE@SUPPY may be a suitable A3 PET tracer for use in humans.

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Imaging Studies with A2A Receptor Antagonists

Tavares

Barret

Seibyl

et al. 2015

Current Topics in Neurotoxicity

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Automatisation and First Evaluation of [18F]FE@SUPPY:2, an Alternative PET-Tracer for the Adenosine A3 Receptor: A Comparison with [18F]FE@SUPPY

Cited by 8 publications

References 26 publications

[18F]FE@SUPPY: a suitable PET tracer for the adenosine A3 receptor? An in vivo study in rodents

[18F]FE@SUPPY: a suitable PET tracer for the adenosine A3 receptor? An in vivo study in rodents

Hide and seek: a comparative autoradiographic in vitro investigation of the adenosine A3 receptor

Imaging Studies with A2A Receptor Antagonists

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