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

Abstract

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).

Imaging of Muscarinic Receptors in the Central Nervous System

“…In one approach, a ligand that is selective in vitro, AF-DX 116 [11-(((2-(diethylamino)-methyl)-1-piperidinyl) acetyl)-5-11-dihydro-6H-pyrido(2,3) (1,4) benzodiazepin-6-one], was modified to increase its BBB permeability while maintaining subtype selectivity [69]. In the second approach, non-subtype selective RS IQNB which crosses into the brain, was modified to increase its subtype selectivity [70,71]. Neither of these approaches has yielded a compound sensitive to changes in a subtype of the muscarinic receptor.…”

In vivo metabolic studies of thetrans-(R,R) isomer of radioiodinated IQNP: A new ligand with high affinity for the M1 muscarinic-cholinergic receptor

“…The uptake of radioiodinated IQNP in those regions of rat brain known to be rich in the muscarinic receptors is blocked by pretreatment with IQNB [9]. Our goal in the current study was to evaluate the metabolism of the radioiodinated E-(R,R) isomer in rat tissues in vivo.…”

“…was prepared and purified as previously described in 65.6% radiochemical yield with radiopurity of greater than 98% [9]. Specific activity was determined as described previously to be greater than 1200 mCi/~mol.…”

“…1) of 3-quinuclidinyl benzilate (QNB), and is radioiodinated in high yield (>60%) with high specific activity from a tributylstannyl derivative. We have recently reported in vitro high-affinity binding of this ligand to mAchR and the in vivo selectivity and specificity for mAchR [9]. Since carbon-3 of the quinuclidinyl moiety and carbon-2 of the acetate moiety are asymmetric centers and the vinylic iodide can have either the E or Z configuration, eight different isomeric combinations of "IQNP" are thus possible.…”

Synthesis and In Vitro Evaluation of Novel Nortropane Derivatives as Potential Radiotracers for Muscarinic M2 Receptors

“…Many attempts have been made to develop muscarinic receptor subtype selective radiotracers [10–12]. Currently, amongst the most promising of these potential tracers is [ 18 F]FP-TZTP [10, 13, 14], which has selectivity for the muscarinic M 2 receptor [15] and has been applied successfully in several human PET studies [16–18].…”