Uptake and retention kinetics of para-fluorine-18-fluorobenzylguanidine in isolated rat heart.
Para-[18F]fluorobenzylguanidine ([18F]PFBG) is a newly developed tracer for imaging myocardial sympathetic neuronal innervation. This study investigated the uptake and retention mechanisms of [18F]PFBG in perfused, isolated rat heart.


METHODS
Fluorine-18-PFBG was administered to working rat hearts within the perfusion medium at a constant activity concentration (1.5-2 MBq/liter) for 8 min, followed by a washout period (50 min). External scintillation probes with coincidence detection circuitry were used to measure myocardial radioactivity. Six groups of hearts (n = 6, except in Group 6) were studied: (Group 1) control; (Group 2) 100 nM desipramine (DMI); (Group 3) 0.8 microM SKF550; (Group 4) DMI + SKF550; (Group 5) SKF550 + 1.0 microM Ro 4-1284; and (Group 6) SKF550 with DMI chase at 30 min (n = 4).


RESULTS
Groups 2, 3 and 4 showed a mean reduction of 19% (uptake-1 blockade), 58% (uptake-2 blockade) and 95% (uptake-1 and uptake-2 blockade) in uptake rates, respectively, compared with control (p < 0.01). A further 33% reduction in the uptake rate was noted with vesicular transport inhibition (Group 5 compared with 3, p = 0.054). Biphasic clearance consisting of rapid (T1/2 = 5.32 +/- 1.1 min) and slow (T1/2 = 35.2 +/- 9.6 min) components were noted in control hearts. The rapid (T1/2 = 1.6 +/- 0.3 min) and slow (T1/2 = 10.9 +/- 1.4 min) clearance rates were accelerated (p < 0.0001) in Group 5 compared to control. DMI chase conditions (Group 6) caused an inhibition of [18F]PFBG washout (p = 0.004) suggesting a role for reverse transport through the uptake-1 carrier.


CONCLUSIONS
Fluorine-18-PFBG is specifically accumulated by sympathetic nerve terminals. However, further work is recommended in humans to evaluate the potential implications of specific extraneuronal uptake of [18F]PFBG through the uptake-2 mechanism.
Berry
C R
CR
Department of Anatomy, Physiological Sciences and Radiology, North Carolina State University, College of Veterinary Medicine, Raleigh 27606, USA.
Garg
P K
PK
Zalutsky
M R
MR
Coleman
R E
RE
DeGrado
T R
TR
D012369:2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy- / Q000494:pharmacology; D000818:Animals; D003891:Desipramine / Q000494:pharmacology; D005260:Female; D005449:Fluorenes / Q000494:pharmacology; D005464:Fluorobenzenes / Q000493:pharmacokinetics; D006146:Guanidines / Q000493:pharmacokinetics; D006321:Heart / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000294:innervation; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000000981:diagnostic imaging / Q000378:metabolism
C101472:4-fluorobenzylguanidine; D005449:Fluorenes; D005464:Fluorobenzenes; D006146:Guanidines; D012369:2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-; C102994:SK&F 550; D003891:Desipramine