Monkey, rat, and first in human evaluation of [18F]PF-06445974, a PET radioligand that preferentially labels phosphodiesterase 4B

1054 Introduction: Phosphodiesterase-4 (PDE4) metabolizes and terminates the actions of the second messenger cyclic adenosine monophosphate (cAMP). PDE4 has four isozymes: A, B, C, and D. PDE4B and PDE4D have the highest expression in brain and are linked to cognitive deficits as well as major depressive disorder (MDD). This PET study assessed the newly developed PDE4B-selective radioligand [18F]PF-06445974 in rats, rhesus monkeys and, for the first time, humans. A concomitant goal was to determine whether [18F]PF-06445974 could accurately quantify PDE4 in human brain. Methods: In two human subjects, two whole body PET scans for radiation exposure dosimetry and three brain PET scans for specific PDE4B quantification were performed. In the pharmacokinetic analysis, target enzyme density was quantified as total distribution volume (VT) using the two-tissue compartment model and serial concentrations of parent radioligand in arterial plasma. In one male rhesus monkey, four PET whole body scans were performed on different days. The first scan was acquired under baseline conditions, and rolipram (1.0 mg/kg), a PDE4 inhibitor, was administered IV in the second scan. The same baseline and blocked paradigms were repeated with PF-06445974 (0.1 mg/kg) as the blocking drug. Finally, brain PET scans were conducted in four rats. Concentration of radioactivity as standardized uptake value (SUV) was compared across conditions and species. Results: [18F]PF-06445974 readily entered human brain and showed widespread distribution, with lower binding in cerebellum. VT was well identified in all examined brain regions, and VT calculated from the first 90 min of scan data fell within 10%. VT was highest in thalamus and striatum, broadly matching human brain RNA expression. Whole-body imaging in the two humans and one monkey was notable for early distribution in the blood pool, accumulation in target organs (i.e., brain, lung), and excretion via urinary tract. Doses in the two humans were 19.6 and 19.3 μSV/MBq, respectively, similar to the value extrapolated from monkey (16.5 μSv/MBq). In monkey blocking scans, both drugs substantially blocked brain uptake; at 60 min, rolipram blocked 78% of uptake and PF-06445974 blocked 92%. However, for the rolipram-blocked scan, radioactivity in brain increased after 20 min and returned to baseline by the end of the scan. Rats showed a similar pattern to monkey. To assess whether this was due to radiometabolite in brain or rapid rolipram clearance, a second rolipram dose was injected as a displacing agent at 120 min in a rat that had undergone pre-injection of 1 mg/kg iv. This repeat rolipram dose replenished rolipram concentrations in brain and restored its ability to block radioligand binding, proving that no radiometabolite entered rat or monkey brain. Conclusions: [18F]PF-06445974 successfully imaged and quantified PDE4B in human brain. No radiometabolite contamination occurred, reflecting parent radioligand binding to PDE4 in brain. In nonhuman primates,, rolipram washed out more quickly than PF-06445974. Fig.1 In human brain, [18F]PF-06445974 had widespread distribution, with high uptake in striatum and thalamus. Fig.2 In human brain, two-tissue compartment modeling with plasma parent input was well-fitted (A). Distribution volume (VT) was well identified and stable (B).