UNLABELLED

There have been few radiotracers for imaging adrenergic receptors in brain by PET, but none has advanced for use in human studies. We developed a radiosynthesis for the alpha(2)-adrenergic antagonist (11)C-yohimbine and characterized its binding in living pigs. As a prelude to human studies with (11)C-yohimbine, we determined the whole-body distribution of (11)C-yohimbine and calculated its dosimetry.

METHODS

Yorkshire x Landrace pigs weighing 35-40 kg were used in the study. Baseline and postchallenge PET recordings of (11)C-yohimbine in pig brain were conducted for 90 min, concurrent with arterial blood sampling, and with yohimbine and RX821002 as pharmacologic interventions. (15)O-Water scans were performed to detect changes in cerebral perfusion. The PET images were manually coregistered to an MR atlas of the pig brain. Maps of the (11)C-yohimbine distribution volume ([V(d)] mL g(-1)) in brain were calculated relative to the arterial input function.

RESULTS

Whole-body scans with (11)C-yohimbine revealed high accumulation of radioactivity in kidney, intestine, liver, and bone. The estimated human dose was 5.6 mSv/GBq, a level commonly accepted in human PET studies. Brain imaging showed baseline values of V(d) ranging from 1.9 in medulla, 3.0 in cerebellum, and to 4.0 in frontal cortex. Coinjection with nonradioactive yohimbine (0.07 mg/kg) reduced V(d) globally to approximately 1.5-2 mL g(-1). A higher yohimbine dose (1.6 mg/kg) was without further effect on self-displacement. Very similar results were obtained by displacement with the more selective alpha(2)-adrenergic antagonist RX821002 at doses of 0.15 and 0.7 mg/kg. Cerebral blood flow was globally increased 43% after administration of RX821002. Notable features of (11)C-yohimbine are a lack of plasma metabolism over 90 min and a rapid approach to equilibrium binding in brain.

CONCLUSION

The new radiotracer (11)C-yohimbine seems well suited for PET investigations of alpha(2)-adrenergic receptors in brain and peripheral structures, with the caveat that displaceable binding was present in cerebellum and throughout the brain.