RT Journal Article
SR Electronic
T1 Radiosynthesis and microPET evaluation of (<em>S</em>,<em>R</em>)-[<sup>11</sup>C]EPMMI and (<em>S</em>)-[<sup>11</sup>C]FDBMB as norepinephrine transporter imaging agents
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1751
OP 1751
VO 54
IS supplement 2
A1 Fanxing Zeng
A1 Ronald Voll
A1 Aaron Smith
A1 Larry Williams
A1 Mark Goodman
YR 2013
UL http://jnm.snmjournals.org/content/54/supplement_2/1751.abstract
AB 1751 Objectives Attempts to image the norepinephrine transporter (NET) in living systems with PET have so far met with limited success due to the lack of effective radioligands. (S,R)1-(2-Ethylphenoxy)-2-((methylamino)methyl)-dihydroxyindane (EPMMI) and (2S)-(4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]1-(methylamino)butan-2-ol (FDBMB) are potent inhibitors of norepinephrine reuptake, with low nanomolar hNET potency (IC50 = 1.5 nM and 1.2 nM, respectively) and high selectivity for hNET over hSERT and hDAT (&gt;600-fold). We aimed to label these two compounds with carbon-11 for evaluation as radioligands for imaging NET in living brain with PET. Methods (S,R)-EPMMI and (S)-FDBMB, and their corresponding normethyl precursors were synthesized via multi-step synthetic approaches. The radiochemical syntheses were performed by simple N-methylation of the corresponding normethyl precursors with no-carrier-added [11C]CH3I in DMF. Distribution coefficients of EPMMI and FDBMB were measured between 1-octanol and phosphate buffer at PH 7.4. MicroPET imaging studies were conducted in rats to evaluate the ability of the candidate compounds to penetrate the blood brain barrier and to label NET. Results (S,R)-[11C]EPMMI was obtained in 38-51% decay-corrected radiochemical yield, whereas (S)-[11C]FDBMB was obtained in 18-25% radiochemical yield, with radiochemical purity of &gt;98% and a specific activity of 0.6-1.2 Ci/µmol. EPMMI and FDBMB display moderate lipophilicity with log P7.4 of 2.54 and 1.92, respectively. Coregistration of the microPET image with microCT demonstrated that both radiotracers showed poor brain availability and the focal uptake of radioactivity was in pituitary gland. Conclusions Although both compounds displayed high affinity and selectivity for the human NET in vitro, these compounds did not enter the central nervous system in adequate amounts to be used in PET imaging studies.