Comparison of the pharmacokinetics of different analogs of 11C-labeled TZTP for imaging muscarinic M2 receptors with PET.
BACKGROUND
The only radiotracer available for the selective imaging of muscarinic M2 receptors in vivo is 3-(3-(3-[18F]fluoropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine) ([18F]FP-TZTP). We have prepared and labeled 3-(3-(3-fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridne (FP-TZTP, 3) and two other TZTP derivatives with 11C at the methylpyridine moiety to explore the potential of using 11C-labeled FP-TZTP for positron emission tomography imaging of M2 receptors and to compare the effect of small structural changes on tracer pharmacokinetics (PK) in brain and peripheral organs.


METHODS
11C-radiolabeled FP-TZTP, 3-(3-propylthio)-TZTP (6) and 3,3,3-(3-(3-trifluoropropyl)-TZTP (10) were prepared, and log D, plasma protein binding (PPB), affinity constants, time-activity curves (TACs), area under the curve (AUC) for arterial plasma, distribution volumes (DV) and pharmacological blockade in baboons were compared.


RESULTS
Values for log D, PPB and affinity constants were similar for 3, 6 and 10. The fraction of parent radiotracer in the plasma was higher and the AUC lower for 10 than for 3 and 6. TACs for brain regions were similar for 3 and 6, which showed PK similar to the 18F tracer, while 10 showed slower uptake and little clearance over 90 min. DVs for 3 and 6 were similar to the 18F tracer but higher for 10. Uptake of the three tracers was significantly reduced by coinjection of unlabeled 3 and 6.


CONCLUSIONS
Small structural variations on the TZTP structure greatly altered the PK in brain and behavior in blood with little change in the log D, PPB or affinity. The study suggests that 11C-radiolabeled 3 will be a suitable alternative to [18F]FP-TZTP for translational studies in humans.
Reid
Alicia E
AE
Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. areid@bnl.gov
Ding
Yu-Shin
YS
Eckelman
William C
WC
Logan
Jean
J
Alexoff
David
D
Shea
Colleen
C
Xu
Youwen
Y
Fowler
Joanna S
JS
D000818:Animals; D019540:Area Under Curve; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging; D002250:Carbon Radioisotopes / Q000097:blood / Q000493:pharmacokinetics*; D054313:Drug Agonism; D005462:Fluorine Radioisotopes / Q000097:blood / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate; D051379:Mice; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods; D011725:Pyridines / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D011869:Radioligand Assay / Q000379:methods*; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D014018:Tissue Distribution
C530437:3-(3-(3-trifluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; C481718:3-(3-(propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D011725:Pyridines; D043585:Receptor, Muscarinic M2; D013830:Thiadiazoles; D013844:Thiazoles; C115177:FP-TZTP