(18)F-FBnTP is a mitochondria-targeting PET radiopharmaceutical responsive to alterations in membrane potential with voltage-dependent performance similar to that of (3)H-TPP. (18)F-FBnTP is a promising new voltage sensor for detection of physiological and pathological processes associated with mitochondrial dysfunction, such as apoptosis, using PET.

Myocardial perfusion imaging plays an important role in clinical management of coronary artery disease, but the most commonly used radionuclides significantly underestimate the severity of coronary artery stenosis. The objective of this study was to evaluate the potential clinical utility of the PET compound 18 F-fluorobenzyl triphenyl phosphonium ( 18 F-FBnTP) and characterize its capacity to assess the severity of coronary artery stenosis in a canine model in vivo and ex vivo. Methods: 18 F-FBnTP myocardial uptake was measured in 17 dogs with various degrees of stenosis of the left anterior descending (LAD) or circumflex (LCx) coronary arteries during adenosine vasodilation, using dynamic PET and g-well counting. True myocardial blood flow in ischemic (IS) and nonischemic (NIS) beds of the left ventricle was determined with radioactive microspheres. 18 F-FBnTP and 99m Tc-tetrofosmin activities were compared in 8 dogs ex vivo. Results: The quantitative assessment of the perfusion defect was significantly (P , 0.03) more accurate with 18 F-FBnTP than with 99m Tc-tetrofosmin, in mild (IS/NIS; 0.72 6 0.08, 0.93 6 0.07, respectively, mean 6 SE) and severe stenosis (0.42 6 0.05, 0.64 6 0.08, respectively), compared with microsphere flow (mild, 0.43 6 0.06; severe, 0.22 6 0.04). The IS/NIS ratio of both radionuclides correlated linearly with microsphere flow disparity with a similar slope. Flow defect contrast was 2.7 times greater for 18 F-FBnTP than for 99m Tc-tetrofosmin, as inferred from the regression line intercept (0.14 vs. 0.38, respectively). The 18 F-FBnTP PET IS/NIS ratio (mild, 0.70 6 0.04; severe, 0.46 6 0.02), did not differ statistically (P $ 0.330) from that measured ex vivo. A nearly identical qualitative and quantitative estimate of stenosis severity was obtained by early, short (5-15-min) and delayed, prolonged (30-60-min) 18 F-FBnTP PET scans. The stenotic area measured by PET was 16% smaller than that defined by tissue staining. Conclusion: 18 F-FBnTP PET is a promising new technology for rapid noninvasive detection and assessment of perfusion defect severity in the myocardium.

purification, and formulation was 56, 82, and 79 min with an average radiochemical yield of 12, 6 and 15%, respectively (not corrected for decay). The average specific radioactivity for the three radiolabeled compounds was 14.9 GB q/mmole (403 mCi/ mmole) at end of synthesis (EOS).

Recently, we have developed the positron emitting radiotracer N1'-([11C]methyl)naltrindole ([11C]MeNTI) and demonstrated its high selectivity for delta opioid receptors in the mouse brain [Lever et al. (1992) Eur. J. Pharmacol., 216:449-450]. In the present study, we examined the selectivity of [11C]MeNTI for the delta opioid receptor in the human brain, using positron emission tomography (PET). The regional kinetics and distribution as well as the pharmacology confirmed the selectivity of [11C]MeNTI for delta opioid receptor in the human brain. First, the regional kinetics of [11C]MeNTI are in accordance with the density of the delta opioid receptor. Rapid washout in receptor-poor areas and prolonged retention in receptor-rich areas were observed. Second, the regional distribution of [11C]MeNTI correlated well (r = 0.91) with the in vitro distribution of delta opioid sites but not with mu or kappa site densities (r < or = 0.008 or r < or = 0.014, respectively). [11C]MeNTI binding was highest in regions of the neocortex (insular, parietal, frontal, cingulate, and occipital), caudate nucleus, and putamen. Binding was intermediate in the amygdala and lowest in the cerebellum and thalamus. Third, studies using the competitive antagonist naltrexone demonstrated the inhibition of [11C]MeNTI binding. Naltrexone inhibition of [11C]MeNTI binding was most effective in delta receptor-rich regions, and its inhibitory potency correlated well (r = 0.88) with the regional distribution of delta opioid sites. [11C]MeNTI is the first radioligand which selectively labels delta opioid receptors in vivo in the human brain following systemic administration. The availability of [11C]MeNTI will enable a receptor specific analysis of the role of [11C]MeNTI receptors in normal and abnormal human brain.

Apoptosis is a key mechanism in numerous pathologies. However, there are no effective noninvasive means available for an early detection and quantitative assessment of evolution dynamics of the apoptotic process. Here, we have characterized the ability of the novel PET voltage sensor 18 F-fluorobenzyl triphenyl phosphonium ( 18 F-FBnTP) to quantify the time-dependent apoptotic action of the taxanes paclitaxel and docetaxel in vitro and in vivo. Methods: The duration-dependent treatment effect of paclitaxel on 18 F-FBnTP uptake was assayed in human MDA-MB-231 breast carcinoma cells. The expression of the proapoptotic Bax and antiapoptotic Bcl-2 mitochondrial proteins, release of the apoptogen cytochrome c, and activation of executioner caspase-3 were determined by Western blotting. The fraction of viable cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. The effect of docetaxel on 18 F-FBnTP and 18 F-FDG uptake in orthotopic prostate tumors in mice was compared. Results: 18 F-FBnTP cellular uptake in viable cells declined linearly with the increasing duration of paclitaxel treatment, from 3 to 24 h, and plateaued at 48 h. The extent of decrease of 18 F-FBnTP correlated strongly with the Bax-to-Bcl-2 ratio (R 2 5 0.83) and release of cytochrome c (R 2 5 0.92), but preceded in time the caspase-3 cleavage. The P-glycoprotein blocker verapamil did not interfere with 18 F-FBnTP cellular uptake. 18 F-FBnTP prostate tumor contrast was greater than 18 F-FDG prostate tumor contrast. Docetaxel caused a marked decrease (52.4%) of 18 F-FBnTP tumor uptake, within 48 h, whereas 18 F-FDG was much less affected (12%). Conclusion: The voltage sensor 18 F-FBnTP is a viable means for quantification of paclitaxel pharmacodynamics. 18 F-FBnTP permits the detection of paclitaxel apoptotic action in vivo earlier than does 18 F-FDG. 18 F-FBnTP may afford a novel approach for early detection and quantitative assessment of the cumulative-effect kinetics of proapoptotic drugs and conditions using PET.

18 F-fluorobenzyl triphenyl phosphonium (FBnTP) has recently been introduced as a myocardial perfusion PET agent. We used a rat model of transient coronary occlusion to determine the stability of the perfusion defect size over time and the magnitude of redistribution. Methods: Wistar rats (n 5 15) underwent thoracotomy and 2-min occlusion of the left coronary artery (LCA), followed by reperfusion. During occlusion, 18 F-FBnTP (92.5 MBq) and 201 Tl-thallium chloride (0.74 MBq) were injected intravenously. One minute before the animals were sacrificed at 5, 45, and 120 min after reperfusion, the LCA was occluded again and 2% Evans blue was injected intravenously to determine the ischemic territory. The hearts were excised, frozen, and sliced for serial dual-tracer autoradiography and histology. Dynamic in vivo 18 F-FBnTP PET was performed on a subgroup of animals (n 5 4). Results: 18 F-FBnTP showed stable ischemic defects at all time points after tracer injection and reperfusion. The defects matched the blue dye defect (y 5 0.97x11.5, R 2 5 0.94, y 5 blue-dye defect, x 5 18 F-FBnTP defect). Count density analysis showed no defect fill-in at 45 min but slightly increased activity at 120 min (LCA/remote uptake ratio 5 0.19 6 0.02, 0.19 6 0.05, and 0.34 6 0.06 at 5, 45, and 120 min, respectively, P , 0.05). For comparison, 201 Tl showed complete redistribution at 120 min (LCA/remote 5 0.42 6 0.04, 0.72 6 0.03, and 0.97 6 0.05 at 5, 45, and 120 min, respectively, P , 0.001). Persistence of the 18 F-FBnTP defect over time was confirmed by in vivo dynamic small-animal PET. Conclusion: In a transient coronary occlusion model, perfusion defect size using the new PET agent 18 F-FBnTP remained stable for at least 45 min and matched the histologically defined ischemic area. This lack of significant redistribution suggests a sufficient time window for future clinical protocols with tracer injection remote from the scanner, such as in a stress testing laboratory or chest pain unit. PET myocardial perfusion imaging is increasingly entering the clinical arena as a highly accurate technique for the workup of coronary artery disease (1,2). When compared with standard SPECT, it provides better temporal and spatial resolution, higher sensitivity for tracer detection, and robust correction of attenuation artifacts (3,4). The currently established PET myocardial perfusion tracers include 82 Rb-rubidium chloride, 13 N-ammonia, and 15 Owater, but their short radioactive half-lives (76 s, 10 min, and 2.1 min, respectively) require expensive on-site production by a cyclotron or commitment to a dedicated generator. Additionally, a physical-exercise stress test is not practical because of the rapid decay of these tracers.18 F-fluorobenzyl triphenyl phosphonium (FBnTP) is one of several recently introduced 18 F-labeled perfusion tracers. It is a cation with a mechanism of uptake similar to 99m Tctetrofosmin and 99m Tc-sestamibi and has shown promising properties such as high cardiac uptake and retention in animal models (5-8). Because of t...

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The involvement of opioid neurotransmitter systems in seizure mechanisms is well documented. In previous positron emission tomography (PET) studies in patients with unilateral temporal lobe epilepsy, we have found evidence for differential regulation of the opioid-receptor subtypes. The present study extends our previous observations to delta-opioid receptors by using the delta-receptor-selective antagonist [11C]methylnaltrindole ([11C]MeNTI). Paired measurements of delta- and mu-opioid receptor binding and metabolic activity were performed with PET using [11C]MeNTI and [11C]carfentanil ([11C]CFN) and [18F]fluorodeoxyglucose ([18F]FDG), respectively. Binding of [11C]MeNTI and [11C]CFN increased and [18F]FDG uptake decreased in the temporal cortex (TC) ipsilateral to the focus. Decreases in [18F]FDG uptake were more widespread regionally than were increases in opioid receptors. Increases in the delta- and mu-receptor binding showed different regional patterns. Increases in mu-receptor binding were confined to the middle aspect of the inferior TC, whereas binding of delta receptors increased in the mid-inferior TC and anterior aspect of the middle and superior TC. The increase in delta receptors suggests their anticonvulsant action, as previously shown for the delta-receptor subtype, whereas the different regional pattern of receptor alterations suggest the distinct roles of different opioid-receptor subtypes in seizure phenomena.