Radiolabeled phenethylguanidines: novel imaging agents for cardiac sympathetic neurons and adrenergic tumors.

The norepinephrine transporter (NET) substrates [123I]-m-iodobenzylguanidine (MIBG) and [11C]-m-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. [11C]Phenethylguanidine ([11C]1a) and 12 analogues ([11C]1b-m) were synthesized and evaluated as radiotracers with improved kinetics for quantifying cardiac nerve density. In isolated rat hearts, neuronal uptake rates of [11C]1a-m ranged from 0.24 to 1.96 mL min-1 (g wet wt)-1, and six compounds had extremely long neuronal retention times (clearance T1/2 > 20 h) due to efficient vesicular storage. Positron emission tomography (PET) studies in nonhuman primates with [11C]1e, N-[11C]guanyl-m-octopamine, which has a slow NET transport rate, showed improved myocardial kinetics compared to HED. Compound [11C]1c, [11C]-p-hydroxyphenethylguanidine, 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.

Dependence of cardiac 11C-meta-hydroxyephedrine retention on norepinephrine transporter density.

UNLABELLED: The norepinephrine analog (11)C-meta-hydroxyephedrine (HED) is used with PET to map the regional distribution of cardiac sympathetic neurons. HED is rapidly transported into sympathetic neurons by the norepinephrine transporter (NET) and stored in vesicles. Although much is known about the neuronal mechanisms of HED uptake and retention, there is little information about the functional relationship between HED retention and cardiac sympathetic nerve density. The goal of this study was to characterize the dependence of HED retention on nerve density in rats with graded levels of cardiac denervation induced chemically with the neurotoxin 6-hydroxydopamine (6-OHDA). METHODS: Thirty male Sprague-Dawley rats were divided into 6 groups, and each group was administered a different dose of 6-OHDA: 0 (controls), 7, 11, 15, 22, and 100 mg/kg intraperitoneally. One day after 6-OHDA injection, HED (3.7-8.3 MBq) was injected intravenously into each animal and HED concentrations in heart and blood at 30 min after injection were determined. Heart tissues were frozen and later processed by tissue homogenization and differential centrifugation into a membrane preparation for in vitro measurement of cardiac NET density. A saturation binding assay using (3)H-mazindol as the radioligand was used to measure NET density (maximum number of binding sites [B(max)], fmol/mg protein) for each heart. RESULTS: In control animals, NET B(max) was 388 +/- 23 fmol/mg protein and HED heart uptake (HU) at 30 min was 2.89% +/- 0.35 %ID/g (%ID/g is percentage injected dose per gram tissue). The highest 6-OHDA dose of 100 mg/kg caused severe cardiac denervation, decreasing both NET B(max) and HED HU to 8% of their control values. Comparing values for all doses of 6-OHDA, HED retention had a strong linear correlation with NET density: HU = 0.0077B(max) -0.028, r(2) = 0.95. CONCLUSION: HED retention is linearly dependent on NET density in rat hearts that have been chemically denervated with 6-OHDA, suggesting that HED retention is a good surrogate measure of NET density in the rat heart. This finding is discussed in relation to clinical observations of the dependence of HED retention on cardiac nerve density in human subjects using PET.