Initial Evaluation of an Adenosine A(2A) Receptor Ligand, C-11-Preladenant, in Healthy Human Subjects

C-11-preladenant is a selective antagonist for mapping of cerebral adenosine A(2A) receptors (A(2A)Rs) by PET. This is a first-in-human study to examine the safety, radiation dosimetry, and brain imaging of C-11-preladenant in healthy human subjects. Methods: Dynamic C-11-preladenant PET scans (90 min) were obtained in 5 healthy male subjects. During the scan, arterial blood was sampled at various time intervals, and the fraction of the parent compound in plasma was determined. For anatomic coregistration, T1-weighted MRI was performed. The total distribution volume (VT) was estimated using 1- and 2-tissue-compartment models (1T and 2T, respectively). The distribution volume ratio (DVR) was calculated from VT of target and reference region and obtained with a noninvasive Logan graphical reference tissue method (t* = 30 min). The applicability of a shortened protocol as an alternative to the 90-min PET scan was investigated. Tracer biodistribution and dosimetry were determined in 3 healthy male subjects, using serial whole-body PET scans acquired over 2 h after C-11-preladenant injection. Results: There were no serious adverse events in any of the subjects throughout the study period. C-11-preladenat readily entered the brain, with a peak uptake in the putamen and head of the caudate nucleus 30-40 min after tracer injection. Other brain regions showed rapid clearance of radioactivity. The regional distribution of C-11-preladenant was consistent with known A(2A)R densities in the brain. At pseudoequilibrium (reached at 40 min after injection), stable target-to-cerebellar cortex ratios of around 3.8-10.0 were obtained. The 2T fit better than the 1T in the low-density A(2A)R regions. In contrast, there were no significant differences between 1T and 2T in the high-A(2A)R-density regions. DVRs in the putamen and head of the caudate nucleus were around 3.8-10.3 when estimated using a Logan graphical reference tissue method with cerebellum as the reference region. PET scanning at 50 or 70 min can provide the stable DVR estimates within 10% or 5% differences at most, respectively. The radioactivity was mainly excreted through the hepatobiliary system after C-11-preladenant injection. As a result, the absorbed dose (mGy/MBq) was highest in the gallbladder wall (mean +/- SD, 17.0 +/- 2.5) and liver (11.7 +/- 2.1). The estimated effective dose for C-11-preladenant was 3.7 +/- 0.4 mSv/MBq. Conclusion: This initial evaluation indicated that C-11-preladenat is suitable for imaging of A(2A)Rs in the brain.