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

Abstract

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.

Figure 1

Structures of norepinephrine and some clinically used sympathetic nerve imaging agents.

Figure 2

A: Comprehensive compartmental model of [¹¹C]HED kinetics in the heart. Arrow thicknesses indicate relative magnitudes of rate constants. K₁ has units of mL/min/g; all other rate constants have units of min^-1. C_p = concentration in plasma; C_E = concentration in extracellular space; C_axo = concentration in neuronal axoplasm; C_ves = concentration in vesicles; NET = norepinephrine transporter; VMAT = vesicular monoamine transporter. B: Comprehensive compartmental model of a tracer with ‘ideal’ kinetic properties for kinetic modeling. C: Simplified compartmental model that could be used to analyze the myocardial kinetics of a PET tracer possessing the ‘ideal’ kinetic properties shown in B.

Figure 3

General structure of [¹¹C]phenethylguanidines and compounds synthesized.

Figure 4

Neuronal uptake and clearance kinetics of [¹¹C]phenethylguanidines in the isolated rat heart. A: Five of the six compounds that exhibited long neuronal retention times. For clarity, compound [¹¹C]1d is not shown due to its similar kinetics with [¹¹C]1k. B: The unsubstituted reference compound [¹¹C]1a and the three analogs with a single ring fluoro-substitution.

Figure 5

Kinetics of [¹¹C]1c in the isolated rat heart under: (a) control conditions; (b) desipramine (DMI) chase to prevent neuronal reuptake during tracer clearance; and (c) reserpine block of vesicular storage.

Figure 6

Kinetics of [¹¹C]1c and its benzylguanidine analog [¹¹C]5 in the isolated rat heart.

Figure 7

Relationship between in vivo uptake of compounds in the left ventricle (LV) of the rat and neuronal uptake rates measured in the isolated rat heart (K_up).

Figure 8

Representative PET images (coronal slice) and corresponding myocardial kinetics of selected compounds in the rhesus macaque monkey. A: [¹¹C]HED, 5.4 mCi injected into a 5.3 kg monkey. B: [¹¹C]1e, 4.9 mCi injected into a 4.7 kg monkey. C: [¹¹C]1b, 4.8 mCi injected into a 5.8 kg monkey. The images are summed images of the data in the final 5 frames of the 15-frame dynamic sequence (15-60 min).

Figure 9

PET image of [¹¹C]1c in a BALB/c nu/nu mouse with a rat pheochromocytoma (PC12) xenograft tumor in the left flank. A dose of 0.34 mCi was injected into the 25 g mouse. The image is a summed image of the data in the final 6 frames of the 12-frame dynamic sequence (15-60 min).

Scheme 1

Scheme 2