Synthesis and preclinical evaluation of [11C]D617, a metabolite of (R)-[11C]verapamil.
OBJECTIVE
(R)-[(11)C]verapamil is widely used as a positron emission tomography (PET) tracer to evaluate P-glycoprotein (P-gp) functionality at the blood-brain barrier in man. A disadvantage of (R)-[(11)C]verapamil is the fact that its main metabolite, [(11)C]D617, also enters the brain. For quantitative analysis of (R)-[(11)C]verapamil data, it has been assumed that the cerebral kinetics of (R)-[(11)C]verapamil and [(11)C]D617 are the same. The aim of the present study was to investigate whether the cerebral kinetics of (R)-[(11)C]verapamil and [(11)C]D617 are indeed similar and, if so, whether [(11)C]D617 itself could serve as an alternative PET tracer for P-gp.


METHODS
[(11)C]D617 was synthesized and its ex vivo biodistribution was investigated in male rats at four time points following intravenous administration of [(11)C]D617 (50 MBq) without (n=4) or with (n=4) pretreatment with the P-gp inhibitor tariquidar (15 mg·kg(-1), intraperitoneally). Brain distribution was further assessed using consecutive PET scans (n=8) before and after pretreatment with tariquidar (15 mg·kg(-1), intravenously), as well as metabolite analysis (n=4).


RESULTS
The precursor for the radiosynthesis of [(11)C]D617, 5-amino-2-(3,4-dimethoxy-phenyl)-2-isopropyl-pentanitrile (desmethyl D617), was synthesized in 41% overall yield. [(11)C]D617 was synthesized in 58%-77% decay-corrected yield with a radiochemical purity of ≥99%. The homogeneously distributed cerebral volume of distribution (V(T)) of [(11)C]D617 was 1.1, and this increased 2.4-fold after tariquidar pretreatment.


CONCLUSIONS
V(T) of [(11)C]D617 was comparable to that of (R)-[(11)C]verapamil, but its increase after tariquidar pretreatment was substantially lower. Hence, (R)-[(11)C]verapamil and [(11)C]D617 do not show similar brain kinetics after inhibition of P-gp with tariquidar.
Department of Nuclear Medicine & PET Research, VU University Medical Center, Amsterdam, the Netherlands. jverbeek@rnc.vu.nl
Joost
J
Verbeek
Stina
S
Syvänen
Robert C
RC
Schuit
Jonas
J
Eriksson
Elizabeth C
EC
de Lange
Albert D
AD
Windhorst
Gert
G
Luurtsema
Adriaan A
AA
Lammertsma
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D002250:Carbon Radioisotopes; D060326:Chemistry Techniques, Synthetic; D007700:Kinetics; D008297:Male; D009570:Nitriles / Q000138:chemical synthesis* / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D051381:Rats; D014700:Verapamil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D009570:Nitriles; C482241:2-(3,4-dimethoxyphenyl)-5-amino-2-isopropylvaleronitrile; D014700:Verapamil