Synthesis of 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles and their in vitro and in vivo evaluation as imaging agents for amyloid plaque.

A series of novel 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles was synthesized and their potential as imaging probes for Alzheimer's Disease (AD)-related amyloid plaque was evaluated in vitro and in vivo. In vitro binding affinities for Abeta1-40 peptide of several of these compounds were in the low-nanomolar range . The lowest K(i) of 9.

Synthesis, radiolabeling and baboon SPECT imaging of 2beta-carbomethoxy-3beta-(3'-[(123)I]iodophenyl)tropane ([(123)I]YP256) as a serotonin transporter radiotracer.

To develop a potential SPECT probe to evaluate the integrity of the serotoninergic system (5-HTT) whose dysfunction is linked to several disease conditions such as Parkinson's disease, Alzheimer's disease and depression, we report the synthesis, radiolabeling and in vivo baboon imaging of 2beta-carbomethoxy-3beta-(3'-[(123)I]iodophenyl) tropane (YP256, 6). The radiolabeling was performed by iododestannylation using sodium [(123)I]iodide and peracetic acid. Although the ligand displayed high selectivity for 5-HTT over dopamine transporter in vitro, SPECT imaging in baboons did not reveal selective 5-HTT accumulation in brain in vivo.

Chemical fate of the nicotinic acetylcholinergic radiotracer [123I]5-IA-85380 in baboon brain and plasma.

The fate of the nicotinic acetylcholinergic receptor radiotracer [123I]5-IA-85380 ([123I]5-IA) was studied in baboon by analyzing the chemical composition of brain tissue and plasma after intravenous administration of the tracer. Acetonitrile denaturation and high-performance liquid chromatography (HPLC) analysis showed predominantly unchanged (91-98%) parent tracer in all brain tissues examined, compared to significant metabolism (23% parent) in the plasma at 90 min postinjection, and control tissue recovery of 95-98%. [123I]5-IA was distributed to the thalamus with a standardized uptake value of 9.

Synthesis and affinity of a possible byproduct of electrophilic radiolabeling of [123I]IBZM.

The iodobenzamide neuroleptic analogue (S)-N-(1-ethylpyrrolidin-2-ylmethyl)-2-hydroxy-5-iodo-6-methoxybenzamide (5-IBZM) was synthesized stereospecifically and its pharmacological properties were compared with the 3-iodo isomer (IBZM) used for imaging D(2) receptors in vivo. The isomer 5-IBZM had 100-fold lower affinity than IBZM and migrated with similar retention time as the byproduct formed during electrophilic iodination of BZM.

Measurement of plasma metabolites of (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine (5-IA-85380), a nicotinic acetylcholine receptor imaging agent, in nonhuman primates.

The iodinated analog (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine of A-85380 is a new potential SPECT tracer specific for the alpha4beta2 subtype nicotinic acetylcholine receptors, which play an important role in neurodegenerative diseases and in tobacco dependence. To evaluate the possibility of using this tracer for the in vivo quantification of these receptors, an accurate measurement of the plasma concentration of the parent compound is necessary. In human or nonhuman primate whole blood as well as in plasma, the parent compound is only stable for approximately 5 min, after which it decomposes.