A one-step radiosynthesis of [¹¹C]methylphenidate

Objectives Carbon-11 labelled d-threo-methylphenidate ([¹¹C-MP) is used to image the dopamine transporter in the human brain with PET. The reported syntheses of [¹¹C]-MP are two-step processes, reacting a protected precursor with [¹¹C]methyl iodide (at 80 ^oC), followed by a deprotection step, with synthesis times of 40-45 minutes after EOB. The goal of the present study was to find a fast, one-step, room-temperature synthesis of [¹¹C]-MP.

Methods Radiosynthesis of [¹¹C]-MP was achieved in a one-step reaction at room temperature using the "loop" method developed in our laboratory. In a typical reaction 0.4 mg of unprotected precursor (d-threo-ritalinic acid) was dissolved in a mixture of DMF and pH 7.4 buffer (0.05 M NaOH/KH₂PO₄) and loaded onto an HPLC loop. [¹¹C]Methyl triflate was then delivered to the loop (5 minute reaction), followed by HPLC purification and formulation (<30 minute overall synthesis time after EOB). Enantiomeric purity was determined by chiral HPLC.

Results The present synthesis of [¹¹C]-MP was achieved without protecting the β-amino functionality through judicious control of the pH to create the zwitter-ionic species, effectively preventing methylation at the nitrogen atom. [¹¹C]-MP was labelled with [¹¹C]methyl triflate in 3% uncorrected radiochemical yield based on starting [¹¹C]CO₂ (850 mCi) and had a specific activity of 1.4 Ci/μmol. This reaction produced 24 mCi of radiochemically pure (>99%) and enantiomerically pure (>98%) [¹¹C]-MP.

Conclusions A fast, one-step synthesis of [¹¹C]-MP was achieved in modest radiochemical yield with good radiochemical and enantiomeric purity via reaction of [¹¹C]methyl triflate with an unprotected precursor at room temperature. Parameter optimization is underway to improve radiochemical yields. This approach demonstrates that unprotected amino acids can be selectively radiolabelled with carbon-11 to prepare [¹¹C]-amino esters.

Research Support CAM