The norepinephrine transporter (NET) substrates [ 123 I]meta-iodobenzylguanidine (MIBG) and [ 11 C] meta-hydroxyephedrine (HED) are used as markers of cardiac sympathetic neurons and adrenergic tumors (pheochromocytoma, neuroblastoma). However, their rapid NET transport rates limit their ability to provide accurate measurements of cardiac nerve density. [ 11 C]Phenethylguanidine ([ 11 C] 1a) and 12 analogs ([ 11 C]1b-m) were synthesized and evaluated as radiotracers with improved kinetics for quantifying cardiac nerve density. In isolated rat hearts, neuronal uptake rates of [ 11 C] 1a-m ranged from 0.24 to 1.96 mL/min/g wet, and six compounds had extremely long neuronal retention times (clearance T 1/2 > 20 hr) due to efficient vesicular storage. PET studies in nonhuman primates with [ 11 C]1e, N-[ 11 C]guanyl-meta-octopamine, which has a slow NET transport rate, showed improved myocardial kinetics compared to HED. Compound [ 11 C]1c, [ 11 C]parahydroxyphenethylguandine, which has a rapid NET transport rate, avidly accumulated into rat pheochromocytoma xenograft tumors in mice. These encouraging findings demonstrate that radiolabeled phenethylguanidines deserve further investigation as radiotracers of cardiac sympathetic innervation and adrenergic tumors.

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Enzymatically dispersed bovine hypothalamic or cortical tissue was maintained in culture in the presence of 3H-labeled amino acids. After such incubation, extracts of cells and of media contained 3H-labeled products that were specifically bound by immobilized affinity-purified antisera to corticotropin (ACTH) and f3-endorphin. The majority of these products eluted in the void volume ( Vo) upon Sephadex G-50 gel fil-

The highly toxic curraremimetic and cholinergic neuron marker (-)-5-iodobenzovesamicol (IBVM) has been labeled with iodine-125 and iodine-123. [125I]IBVM, suitable for animal distribution and ex vivo autoradiographic studies, was synthesized by solid-state exchange; isolated yields were 65-89% with specific activities in the range of 130-200 Ci/mmol. The synthesis of no-carrier-added (-)-5-[125I]IBVM from the corresponding chiral (-)-5-(tri-n-butyltin) derivative using Na125I was evaluated using the oxidants H2O2, peracetic acid and chloramine-T. Both peracetic acid and chloramine-T gave good yields (70-95%). However, when Na123I was utilized, acceptable yields of [123I]IBVM were obtained only with chloramine-T. Use of the latter oxidant did produce 5-chlorobenzovesamicol which was eliminated during HPLC purification. After optimization of the reaction parameters, [123I]IBVM in batch sizes of 10-27 mCi, is routinely obtained with a specific activity of 30-70,000 Ci/mmol, radiochemical purity (> 97%) and chiral purity (> 98%). Isolated radiochemical yields have averaged 71% (N = 40). Distribution analyses of [125I]IBVM and [123I]IBVM in mice 4 h following intravenous administration show essentially equivalent concentrations of the two tracers in the four brain regions sampled. The exceptionally high specific activity of [123I]IBVM has made possible the evaluation of this radiotracer in humans.

The regional mouse brain distribution of a new carbon-11 labeled derivative of vesamicol, [11C]-5-(N-methylamino)benzovesamicol [( 11C]MABV) is reported. Radiotracer concentrations in vivo are in the rank order of striatum greater than cortex greater than hippocampus greater than hypothalamus greater than cerebellum, consistent with reported distributions of other presynaptic cholinergic neuronal markers. In time course studies, striatum/cerebellum and cortex/cerebellum ratios for (-)-[11C]MABV continue to increase to values of 13 and 5, respectively, 75 min after i.v. injection of [11C]MABV. The specific binding in striatum and cortex is lowered by pretreatment with (+/-)-vesamicol, and shows stereoselectivity with lower uptake and lower ratios for the (+)-enantiomer. (-)-enantiomer. (-)-[11C]MABV is proposed as a positron-emitting radioligand for the in vivo study of presynaptic cholinergic neurons.