Comparison of the pharmacokinetics of different analogs of 11C-labeled TZTP for imaging muscarinic M2 receptors with PET

Introduction: The only radiotracer available for the selective imaging of muscarinic M2 receptors in vivo is 3-(3-{3-[F-18]fluoropropyl)thio}-1,2,5 -thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine) ([F-18]FP-TZTP). We have prepared and labeled 3-(3-(3-fluoropropylthio)-1,2,5thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridne (FP-TZTP, 3) and two other TZTP derivatives with C-11 at the methylpyridine moiety to explore the potential of using C-11-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: C-11-radio labeled FP-TZTP, 3-(3-propy]thio)-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 F-18 tracer but higher for 10. Uptake of the three tracers was significantly reduced by coinjection of unlabeled 3 and 6. Conclusion: 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 C-11-radiolabeled 3 will be a suitable alternative to [F-18]FP-TZTP for translational studies in humans. (C) 2008 Elsevier Inc. All rights reserved.