Synthesis and biodistribution of iodine-125-labeled 1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate. A new ligand for the potential imaging of muscarinic receptors by single photon emission computed tomography.
1-Azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)- alpha-phenylacetate (IQNP, 3), an analogue of QNB in which a phenyl ring has been replaced with an iodopropenyl substituent, was prepared and evaluated in vitro and in vivo for m-AChR selectivity and specificity. High specific activity [125]IQNP ([125I]-3) was synthesized in greater than 60% yield utilizing an electrophilic iododestannylation reaction with hydrogen peroxide for the oxidation of iodide. In in vitro receptor binding studies, 3 demonstrated high affinity for M1 (Ki = 0.78 nM), M2 (Ki = 1.06 nM), and M3 (Ki = 0.27 nM) subtypes. In vivo biodistribution studies in female rats [125I]-3 demonstrated high uptake in areas rich in muscarinic receptors such as the brain (cortex and striatum) and the heart. Blocking studies were performed with a series of receptor specific agents and demonstrated that the uptake of [125I]-3 was selective and specific for cerebral muscarinic receptor rich areas and that the binding to m-AChR is reversible. The high-yield preparation and specificity and selectivity of high specific activity [125I]IQNP for muscarinic receptors suggest that this is an attractive new agent for potential imaging of cerebral receptors using single photon tomographic imaging (SPECT).
McPherson
D W
DW
Nuclear Medicine Group, Oak Ridge National Laboratory, Tennessee 37831-6022.
DeHaven-Hudkins
D L
DL
Callahan
A P
AP
Knapp
F F
FF
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007457:Iodine Radioisotopes; D008024:Ligands; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D011813:Quinuclidinyl Benzilate / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
D007457:Iodine Radioisotopes; D008024:Ligands; D011812:Quinuclidines; D011976:Receptors, Muscarinic; C080526:1-azabicyclo(2.2.2)oct-3-yl 2-hydroxy-2-(1-iodo-1-propen-3-yl)-2-phenylacetate; D011813:Quinuclidinyl Benzilate