The features of novel radiotracers, specifically the 5-iodo, 2- and 6- fluoro analogs of A-85380, developed to image the nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) and single photon emission computed tomography (SPECT) have been further investigated in terms of subtype selectivity and toxicity. Detailed kinetic and saturation analyses confirmed that 5-[I-125] iodo- A85380 labels with extremely high affinity a homogeneous population of binding sites, presumably the alpha4-beta2 subtype of nAChRs. Results of competition assays for four different types of receptors demonstrated that the affinity of 5-iodo A-85380 for alpha4-beta2 receptors exceeds its affinity for the mammalian alpha7, muscular, and alpha3-beta4 subtypes by three to five orders of magnitude. Further, 5- [I-125] iodo-A85380 shows no binding in any brain region in knockout mice lacking the beta2 subunit of nAChRs. Collectively, these findings demonstrate that 5-[I-125]iodo-A85380 is superior to other radioligands available for selectively imaging alpha4-beta2 nAChRs. Toxicology studies demonstrated that at relatively high doses these ligands have convulsant properties and affect the cardiovascular system. Convulsions in mice were manifested at doses approximately 5000 times larger than doses needed to image nAChRs, demonstrating that the A-85380-related compounds have a wider margin of safety than new imaging ligands that are derivatives of the toxin epibatidine. In preliminary cardiovascular studies in unanesthetized rats, 5-iodo A-85380 and nicotine produced equivalent, modest transient increases in blood pressure, but only nicotine produced marked decreases in heart rate suggesting 5-iodo A- 85380 may be less cardiotoxic than nicotine. Another goal has been to improve PET/[F-18]fluorodeoxyglucose (FDG) methodology by using venous instead of arterial blood sampling to calculate CMRglc. There was a good agreement between the time curves of FDG and glucose concentration obtained from arterial and venous blood samples and values of CMRglc calculated using arterial and venous blood in anesthetized non human primates (NHPs). Substitution of arterial blood sampling by venous sampling will simplify the experimental procedure as applied to both humans and NHPs without a significant loss of accuracy and expands the ability to conduct multiple PET-FDG studies on the same subject. - radiotracers, positron emission tomography, nicotinic receptors
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