Synthesis and preclinical evaluation of novel PET probes for P-glycoprotein function and expression.
P-glycoprotein (P-gp) is an ATP-dependent efflux pump protecting the body against xenobiotics. A P-gp substrate (7) and an inhibitor (6) were labeled with (11)C, resulting in potential tracers of P-gp function and expression.


METHODS
6 and 7 were labeled using (11)CH(3)I. (11)C-verapamil was prepared as published previously, using (11)C-methyl triflate. MicroPET scans (with arterial sampling) and biodistribution studies were performed in rats pretreated with saline, cyclosporin A (CsA, 50 mg/kg), or cold 6 (15 mg/kg).


RESULTS
The radiochemical yields of (11)C-6 and (11)C-7 were approximately 30% with a total synthesis time of 45 min. Cerebral distribution volumes (DV) of (11)C-6 (2.35 +/- 0.11) and (11)C-7 (1.86 +/- 0.15) in saline-treated rats were higher than of (11)C-verapamil (0.64 +/- 0.12). DVs of (11)C-7 and (11)C-verapamil were significantly increased by CsA (to 5.26 +/- 0.14 and 5.85 +/- 0.32, respectively). The DV of (11)C-6 was reduced by cold 6 (to 1.65 +/- 0.03). Its uptake was also reduced (up to 67%) in several peripheral organs that express P-gp.


CONCLUSIONS
(11)C-7 is a novel tracer of P-gp function with higher baseline uptake than (11)C-verapamil. Upregulation of P-gp function in response to treatment (which is hard to detect with (11)C-verapamil) may be detectable using (11)C-7 and PET. Because (11)C-6 shows specific binding in target organs, this compound is the first PET tracer allowing measurement of P-gp expression.
van Waarde
Aren
A
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, The Netherlands. a.van.waarde@ngmb.umcg.nl
Ramakrishnan
Nisha K
NK
Rybczynska
Anna A
AA
Elsinga
Philip H
PH
Berardi
Francesco
F
de Jong
Johan R
JR
Kwizera
Chantal
C
Perrone
Roberto
R
Cantore
Mariangela
M
Sijbesma
Jurgen W A
JW
Dierckx
Rudi A
RA
Colabufo
Nicola A
NA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D007700:Kinetics; D008297:Male; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D011851:Radioactivity; D051381:Rats; D017208:Rats, Wistar; D013194:Staining and Labeling; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D007546:Isoquinolines; D011849:Radioactive Tracers; C039109:isoquinoline