TY  - JOUR
AU  - Matusch, A.
AU  - Meyer, P. T.
AU  - Bier, D.
AU  - Holschbach, M. H.
AU  - Woitalla, D.
AU  - Elmenhorst, D.
AU  - Winz, O. H.
AU  - Zilles, K.
AU  - Bauer, A.
TI  - Metabolism of the A1 adenosine receptor PET ligand [18F]CPFPX by CYP1A2: implications for bolus/infusion PET studies
JO  - Nuclear medicine and biology
VL  - 33
SN  - 1872-9614
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - PreJuSER-52934
SP  - 891 - 898
PY  - 2006
N1  - Record converted from VDB: 12.11.2012
AB  - The A1 adenosine receptor positron emission tomography (PET) ligand 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX, ) undergoes a fast hepatic metabolism. An optimal design of PET quantitation approaches (e.g., bolus/infusion studies) necessitates the knowledge of factors that influence this metabolism. Metabolites of were separated by radio thin-layer chromatography. Metabolism in vivo, in pooled human liver microsomes and in recombinant human cytochrome isoenzyme preparations was studied. Dynamic PET studies using were performed on three controls and two patients, one treated with the antidepressant and inhibitor of cytochrome CYP1A2 fluvoxamine, the other suffering from liver cirrhosis. CPFPX is metabolized by cytochrome CYP1A2 with high selectivity [KM=1.1 microM (95% confidence interval, or CI, 0.6-2.0 microM) and Vmax=243 pmol min(-1) mg(-1) (95% CI, 112-373 pmol min(-1) mg(-1)) corresponding to 2.4 pmol min(-1) pmol(-1) cytochrome P-450]. This metabolism can competitively be inhibited by fluvoxamine with KI=68 nM (95% CI, 34-138 nM). At least eight compounds found in human plasma and in the CYP1A2 in vitro preparations have an identical migration pattern and account together for >90% and >80% of the respective metabolite yield. Metabolism was considerably delayed in the two patients. In conclusion, is metabolized by cytochrome CYP1A2. Its metabolism is therefore subdued to disease-related or xenobiotic-induced changes of CYP1A2 activity. The identification of the metabolic pathway of 1 allows to optimize image quantification in A1 adenosine receptor PET studies.
KW  - Animals
KW  - Cytochrome P-450 CYP1A2: metabolism
KW  - Cytochromes
KW  - Infusions, Parenteral
KW  - Male
KW  - Metabolic Clearance Rate
KW  - Positron-Emission Tomography: methods
KW  - Rats
KW  - Rats, Inbred F344
KW  - Receptor, Adenosine A1: metabolism
KW  - Xanthines: administration & dosage
KW  - Xanthines: diagnostic use
KW  - Xanthines: pharmacokinetics
KW  - 8-cyclopenta-3-(3-fluoropropyl)-1-propylxanthine (NLM Chemicals)
KW  - Cytochromes (NLM Chemicals)
KW  - Receptor, Adenosine A1 (NLM Chemicals)
KW  - Xanthines (NLM Chemicals)
KW  - cytochrome P-448 (NLM Chemicals)
KW  - Cytochrome P-450 CYP1A2 (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:17045169
UR  - <Go to ISI:>//WOS:000241530100009
DO  - DOI:10.1016/j.nucmedbio.2006.07.006
UR  - https://juser.fz-juelich.de/record/52934
ER  -