@article {Easwaramoorthy1171, author = {Balu Easwaramoorthy and Ramesh Neelamegam and Matthew Palatnik and John Myung and Anissa Abi-Dargham and Mark Slifstein}, title = {Synthesis and in vivo evaluation of a C-11 labeled novel dopamine D1 receptor agonist radioligand in baboon}, volume = {52}, number = {supplement 1}, pages = {1171--1171}, year = {2011}, publisher = {Society of Nuclear Medicine}, abstract = {1171 Objectives Currently, the antagonists 11C-SCH23390 and 11C-NNC112 are the only available PET tracers for imaging dopamine D1 receptors (D1R). Neither is selective for D1R (both also bind to 5HT2A) nor sensitive to affinity states or fluctuations in endogenous dopamine levels. We synthesized a novel D1R agonist radioligand, 2-chloro-7-[11C]methyl-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinolin-3-ol (11C-D1A1), based on a known full D1R agonist chemical structure and its tetracyclic core, and evaluated it with in vivo imaging in a baboon. Methods 11C-D1A1 was successfully synthesized. 3.0 mCi of 11C-D1A1 was injected as a single iv bolus in a baboon (20 Kg). Dynamic PET emission data were acquired for 120 min, reconstructed and evaluated qualitatively. Arterial plasma was collected over the course of the scan and 5 samples were analyzed by HPLC for peripheral metabolism. Results Multi-step synthesis yielded precursor and reference compounds for 11C-D1A1. One-step methylation using 11C-MeI followed by HPLC purification (21\% radiochemical yield) produced 11C-D1A1 with high purity (\>95\%; chemical and radiochemical) and high specific activity (1500 Ci/mmol). The regional brain distribution of 11C-D1A1 was low and homogenous with no specific accumulation of the radioactivity in D1R-rich brain regions. The plasma radioactivity was \< 2\% parent compound 2 min post injection (retention time 7.0 min), and <= 1\% parent compound from 4 - 60 min post-injection. A non-brain penetrable polar compound, which eluted at 3 min, was seen as a major metabolite in all samples. Conclusions Despite very low yields of key intermediates, efficient synthetic routes for a D1R agonist radioligand were developed. 11C-D1A1 was rapidly metabolized in plasma with no significant brain uptake. However, the information obtained from the key intermediate synthesis and metabolite studies can be used as a basis for the future designs of D1R agonist radioligands}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/52/supplement_1/1171}, eprint = {https://jnm.snmjournals.org/content}, journal = {Journal of Nuclear Medicine} }