Positron emission tomography imaging of renal mitochondria is a powerful tool in the study of acute and progressive kidney disease models

Abstract

Mitochondrial dysfunction plays a critical role in the pathogenesis of kidney diseases via ATP depletion and reactive oxygen species overproduction. Nonetheless, few studies have reported the renal mitochondrial status clinical settings, partly due to a paucity of methodologies. Recently, a positron emission tomography probe, 18F-BCPP-BF, was developed to non-invasively visualize and quantitate the renal mitochondrial status in vivo. Here, 18F-BCPP-BF positron emission tomography was applied to three mechanistic kidney disease models in rats: kidney ischemia-reperfusion, 5/6 nephrectomy and anti-glomerular basement membrane glomerulonephritis. In rats with ischemia-reperfusion, a slight decrease in the kidney uptake of 18F-BCPP-BF was accompanied by morphological abnormality of the mitochondria in the proximal tubular cells after three hours of reperfusion, when the kidney function was slightly declined. In 5/6 nephrectomy and rats with anti-glomerular basement membrane glomerulonephritis, the kidney uptake of 18F-BCPP-BF cumulatively decreased with impairment of the kidney function, which was accompanied by a reduction of mitochondrial protein and a pathological tubulointerstitial exacerbation rather than glomerular injury. The 18F-BCPP-BF uptake in the injured kidney was suggested to represent the volume of healthy tubular epithelial cells with normally functioning mitochondria. Thus, this positron emission tomography probe can be a powerful tool for studying the pathophysiological meanings of the mitochondrial status in kidney disease. Mitochondrial dysfunction plays a critical role in the pathogenesis of kidney diseases via ATP depletion and reactive oxygen species overproduction. Nonetheless, few studies have reported the renal mitochondrial status clinical settings, partly due to a paucity of methodologies. Recently, a positron emission tomography probe, 18F-BCPP-BF, was developed to non-invasively visualize and quantitate the renal mitochondrial status in vivo. Here, 18F-BCPP-BF positron emission tomography was applied to three mechanistic kidney disease models in rats: kidney ischemia-reperfusion, 5/6 nephrectomy and anti-glomerular basement membrane glomerulonephritis. In rats with ischemia-reperfusion, a slight decrease in the kidney uptake of 18F-BCPP-BF was accompanied by morphological abnormality of the mitochondria in the proximal tubular cells after three hours of reperfusion, when the kidney function was slightly declined. In 5/6 nephrectomy and rats with anti-glomerular basement membrane glomerulonephritis, the kidney uptake of 18F-BCPP-BF cumulatively decreased with impairment of the kidney function, which was accompanied by a reduction of mitochondrial protein and a pathological tubulointerstitial exacerbation rather than glomerular injury. The 18F-BCPP-BF uptake in the injured kidney was suggested to represent the volume of healthy tubular epithelial cells with normally functioning mitochondria. Thus, this positron emission tomography probe can be a powerful tool for studying the pathophysiological meanings of the mitochondrial status in kidney disease. see commentary on page 51 see commentary on page 51 Translational StatementThe present study demonstrates effective mitochondrial imaging with 2-tert-butyl-4-chloro-5-[6-(4-18F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one (18F-BCPP-BF) in rat kidney disease models. The positron emission tomography (PET) signals are well-correlated to kidney function and are suggested to reflect the mass of remnant functional mitochondria in tubular epithelial cells. Once the safety of the probe and its compatibility with the human kidney have been confirmed, 18F-BCPP-BF can be a powerful tool for analyzing the mitochondrial status quantitatively, directly, and less invasively in clinical settings, thereby improving our understanding of the pathophysiological importance of renal mitochondria and possibly leading to novel diagnoses and therapies. The present study demonstrates effective mitochondrial imaging with 2-tert-butyl-4-chloro-5-[6-(4-18F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one (18F-BCPP-BF) in rat kidney disease models. The positron emission tomography (PET) signals are well-correlated to kidney function and are suggested to reflect the mass of remnant functional mitochondria in tubular epithelial cells. Once the safety of the probe and its compatibility with the human kidney have been confirmed, 18F-BCPP-BF can be a powerful tool for analyzing the mitochondrial status quantitatively, directly, and less invasively in clinical settings, thereby improving our understanding of the pathophysiological importance of renal mitochondria and possibly leading to novel diagnoses and therapies. The kidney is a highly energy-demanding and mitochondria-rich organ.1Che R. Yuan Y. Huang S. et al.Mitochondrial dysfunction in the pathophysiology of renal diseases.Am J Physiol Renal Physiol. 2014; 306: F367-F378Crossref PubMed Scopus (251) Google Scholar Specifically, proximal tubules consume large amounts of energy supplied from mitochondria to handle large amounts of fluid and solutes to maintain homeostasis. Adenosine triphosphate (ATP) production in the proximal tubular epithelial cells mostly depends on mitochondrial oxidative phosphorylation rather than the glycolytic pathway.2Bagnasco S. Good D. Balaban R. et al.Lactate production in isolated segments of the rat nephron.Am J Physiol. 1985; 248: F522-F526PubMed Google Scholar In addition to the physiological role as a powerhouse, mitochondrial dysfunction is often associated with the increased production of reactive oxygen species, which causes tissue damage.3Small D.M. Coombes J.S. Bennett N. et al.Oxidative stress, anti-oxidant therapies and chronic kidney disease.Nephrology (Carlton). 2012; 17: 311-321Crossref PubMed Scopus (332) Google Scholar Indeed, mitochondrial dysfunction is reported to play a critical role in the pathogenesis of kidney diseases such as acute kidney injury (AKI) and chronic kidney disease (CKD).1Che R. Yuan Y. Huang S. et al.Mitochondrial dysfunction in the pathophysiology of renal diseases.Am J Physiol Renal Physiol. 2014; 306: F367-F378Crossref PubMed Scopus (251) Google Scholar,4Hall A.M. Unwin R.J. The not so “mighty chondrion”: emergence of renal diseases due to mitochondrial dysfunction.Nephron Physiol. 2007; 105: 1-10Crossref PubMed Scopus (97) Google Scholar,5Hallan S. Sharma K. The role of mitochondria in diabetic kidney disease.Curr Diab Rep. 2016; 16: 61Crossref PubMed Scopus (54) Google Scholar Thus, much attention has been paid to mitochondria in efforts to understand the pathogenesis of kidney diseases and thereby identify therapeutic targets.6Granata S. Dalla Gassa A. Tomei P. et al.Mitochondria: a new therapeutic target in chronic kidney disease.Nutr Metab (Lond). 2015; 12: 49Crossref PubMed Scopus (81) Google Scholar, 7Martin J.L. Gruszczyk A.V. Beach T.E. et al.Mitochondrial mechanisms and therapeutics in ischaemia reperfusion injury.Pediatr Nephrol. 2019; 34: 1167-1174Crossref PubMed Scopus (33) Google Scholar, 8Szeto H.H. Pharmacologic approaches to improve mitochondrial function in AKI and CKD.J Am Soc Nephrol. 2017; 28: 2856-2865Crossref PubMed Scopus (110) Google Scholar In animal studies, several methods are used to evaluate the intrinsic mitochondrial status of the kidney; however, these have some limitations in quantitative capability and precision. One direct method is to measure the oxygen consumption rate of isolated mitochondria.9Sun L. Yuan Q. Xu T. et al.Pioglitazone improves mitochondrial function in the remnant kidney and protects against renal fibrosis in 5/6 nephrectomized rats.Front Pharmacol. 2017; 8: 545Crossref PubMed Scopus (32) Google Scholar, 10Aparicio-Trejo O.E. Tapia E. Molina-Jijón E. et al.Curcumin prevents mitochondrial dynamics disturbances in early 5/6 nephrectomy: relation to oxidative stress and mitochondrial bioenergetics.Biofactors. 2017; 43: 293-310Crossref PubMed Scopus (50) Google Scholar, 11Thomas J.L. Pham H. Li Y. et al.Hypoxia-inducible factor-1α activation improves renal oxygenation and mitochondrial function in early chronic kidney disease.Am J Physiol Renal Physiol. 2017; 313: F282-F290Crossref PubMed Scopus (24) Google Scholar However, the complicated process of mitochondrial isolation may cause data variation. The mitochondrial morphology (e.g., fragmentation or hyperfusion) is a widely accepted indicator of their functional status.12Galvan D.L. Green N.H. Danesh F.R. The hallmarks of mitochondrial dysfunction in chronic kidney disease.Kidney Int. 2017; 92: 1051-1057Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 13Zhan M. Brooks C. Liu F. et al.Mitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology.Kidney Int. 2013; 83: 568-581Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 14Westermann B. Bioenergetic role of mitochondrial fusion and fission.Biochim Biophys Acta. 2012; 1817: 1833-1838Crossref PubMed Scopus (400) Google Scholar However, electron microscopic analysis of the morphology hardly demonstrates quantitative results. Thus, it is more common to use the amount of mitochondrial proteins or mitochondrial DNAs as quantitative surrogate indicators of the mitochondrial status. In the clinical setting, few studies have reported the renal mitochondrial status. In patients with diabetic nephropathy, the analysis of urinary exosomes demonstrated lower levels of mitochondrial proteins and mitochondrial DNAs that were probably derived from kidneys, and the urinary metabolite profile differed from that of healthy controls, suggesting a dysregulated mitochondrial function in the kidney.15Sharma K. Karl B. Mathew A.V. et al.Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease.J Am Soc Nephrol. 2013; 24: 1901-1912Crossref PubMed Scopus (352) Google Scholar Furthermore, dysfunction of extrarenal mitochondria (e.g., in peripheral blood or muscle) was observed in CKD patients.16Tin A. Grams M.E. Ashar F.N. et al.Association between mitochondrial DNA copy number in peripheral blood and incident CKD in the Atherosclerosis Risk in Communities Study.J Am Soc Nephrol. 2016; 27: 2467-2473Crossref PubMed Scopus (73) Google Scholar, 17Lee J.E. Park H. Ju Y.S. et al.Higher mitochondrial DNA copy number is associated with lower prevalence of microalbuminuria.Exp Mol Med. 2009; 41: 253-258Crossref PubMed Scopus (27) Google Scholar, 18Rao M. Li L. Demello C. et al.Mitochondrial DNA injury and mortality in hemodialysis patients.J Am Soc Nephrol. 2009; 20: 189-196Crossref PubMed Scopus (52) Google Scholar, 19Granata S. Zaza G. Simone S. et al.Mitochondrial dysregulation and oxidative stress in patients with chronic kidney disease.BMC Genomics. 2009; 10: 388Crossref PubMed Scopus (168) Google Scholar, 20Gamboa J.L. Billings 4th, F.T. Bojanowski M.T. et al.Mitochondrial dysfunction and oxidative stress in patients with chronic kidney disease.Physiol Rep. 2016; 4e12780Crossref PubMed Scopus (124) Google Scholar Thus, studies on mitochondrial involvement in kidney diseases are limited, mainly due to a paucity of versatile methods to directly and noninvasively quantify the renal mitochondrial status. We previously developed a novel positron emission tomography (PET) probe, 18F-BCPP-BF, which binds specifically to mitochondrial complex I (MC-I)21Harada N. Nishiyama S. Kanazawa M. et al.Development of novel PET probes, [18F]BCPP-EF, [18F]BCPP-BF, and [11C]BCPP-EM for mitochondrial complex 1 imaging in the living brain.J Labelled Comp Radiopharm. 2013; 56: 553-561Crossref PubMed Scopus (38) Google Scholar even in in vivo studies (Supplementary Figure S1). Unlike currently available PET probes, 18F-BCPP-BF enables kidney imaging with a low level of background due to its favorable pharmacokinetic properties (i.e., a rapid uptake and long retention in kidney tissue).22Tsukada H. Nishiyama S. Fukumoto D. et al.Novel PET probes 18F-BCPP-EF and 18F-BCPP-BF for mitochondrial complex I: a PET study in comparison with 18F-BMS-747158-02 in rat brain.J Nucl Med. 2014; 55: 473-480Crossref PubMed Scopus (43) Google Scholar It is therefore preferable to the noninvasive evaluation and quantification of the renal mitochondrial status. A previous study showed that the renal uptake of 18F-BCPP-BF was reduced in an acetaminophen-induced liver and kidney injury model.23Ohba H. Kanazawa M. Kakiuchi T. et al.Effects of acetaminophen on mitochondrial complex I activity in the rat liver and kidney: a PET study with 18F-BCPP-BF.EJNMMI Res. 2016; 6: 82Crossref PubMed Scopus (5) Google Scholar Because that finding was obtained under drug-induced toxic conditions, in the present study, we further evaluated the clinical usefulness of 18F-BCPP-BF in typical models of kidney disease caused by completely clinical a common of disease in the reperfusion 5/6 nephrectomy and anti-glomerular basement membrane rat typical in oxidative The levels of blood and levels of hours after reperfusion and uptake of 2-tert-butyl-4-chloro-5-[6-(4-18F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one (18F-BCPP-BF) in renal and functional and analysis of the in blood renal blood and represent represent 18F-BCPP-BF positron emission tomography fusion of rats uptake of 18F-BCPP-BF by or the of after hours of represent comparison by of hours of reperfusion by positron emission tomography kidney were from the renal and of the were with and of mitochondrial were from after hours of The blood of animal are in electron of proximal tubular cells in were obtained from and injury after hours of ATP mitochondrial complex complex complex complex complex complex protein complex of this see the of this Figure PET imaging was hours after In the PET a uptake of 18F-BCPP-BF by the liver and of the kidney which to the renal and of the which are in mitochondria. the uptake of 18F-BCPP-BF was reduced in the of the kidney of that in it was not in liver of that in hours of reperfusion, the showed of and The of rats demonstrated of the tubular in the of the the tissue to and or was suggesting that the decreased PET was not due to of the mitochondria-rich tubular in the mitochondrial protein levels in the kidney S1). However, electron microscopic of the of proximal tubular cells the of the that mitochondria were in the were in the We a PET study with 5/6 a of the mitochondrial status between the early and of the 18F-BCPP-BF uptake was evaluated and after In we 5/6 with to the of the on the mitochondrial after the 18F-BCPP-BF uptake was reduced in the of the kidney of that in not in the liver of that in and this 5/6 rats demonstrated kidney disease for 5/6 for for 5/6 for and A demonstrated tubular and the of tubular in the renal of not developed after 5/6 rats developed kidney which was by the of in and in and and PET demonstrated the reduced uptake of 18F-BCPP-BF in the of the remnant kidney of that in and which was more than that in the early of 5/6 The uptake was not reduced in the liver of that in in the 5/6 demonstrated in protein of mitochondrial suggesting the reduction of mitochondrial mass tissue the kidney function which was accompanied by the uptake of 18F-BCPP-BF in the kidney of that in suggesting that the PET the remnant kidney the uptake of kidneys, in the early or showed a with the renal in and Figure uptake of 2-tert-butyl-4-chloro-5-[6-(4-18F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one (18F-BCPP-BF) in 5/6 nephrectomy rats the and functional and analysis of the in blood renal blood and represent represent 18F-BCPP-BF positron emission tomography fusion of 5/6 rats after uptake of 18F-BCPP-BF by or the of represent comparison by or of mitochondrial were from after 5/6 of animal are in of the kidney uptake of 18F-BCPP-BF with blood renal of rats after 5/6 of 18F-BCPP-BF was against or of 5/6 or of the after 5/6 were obtained from 5/6 and from the renal were with and ATP mitochondrial complex complex complex complex complex complex protein complex of this see the of this Figure The of the renal in 5/6 demonstrated in the and tubular than of the and to of developed glomerular fibrosis and were were in we a PET study with the a of glomerulonephritis. PET was in the acute and and after after PET demonstrated the reduced renal uptake of 18F-BCPP-BF of that in and with reduction of the of the liver of that in this the kidney function was in in and the developed in 1 after the of The of the renal demonstrated or glomerular than of and of the In fibrosis was not and were suggesting tubulointerstitial (18F-BCPP-BF) in basement membrane rats the acute and and functional and analysis of the 18F-BCPP-BF positron emission tomography fusion of rats or after uptake of 18F-BCPP-BF by or the of represent or comparison by in blood renal blood and after represent or in the represent represent or of kidney uptake of 18F-BCPP-BF after the with urinary after the of 18F-BCPP-BF was against urinary of or of from renal were with and of mitochondrial were from after positron emission tomography or after the of animal are in ATP mitochondrial complex complex complex complex complex complex protein complex of this see the of this Figure the PET in the the reduced kidney uptake of 18F-BCPP-BF was more of that in The kidney dysfunction further in in and and a of the renal demonstrated the in and the tubular and more than of developed glomerular tubules and were tubulointerstitial It is of that were with the renal (Supplementary Figure and urinary a of renal tubular dysfunction Figure demonstrated that the mitochondrial complex protein levels were slightly decreased in the early decrease more in the were with the protein levels of mitochondrial complex in the kidney of animal (Supplementary and Figure In this study, 18F-BCPP-BF, a new PET probe for was to the kidney mitochondrial status in the and models. In these PET imaging demonstrated a common reduction in the renal uptake of 18F-BCPP-BF, suggesting some in the mitochondrial status was in the process of disease their In the present study demonstrates that the mitochondrial probably reflect the decrease in the mitochondrial mass or in the tubular rather than the glomerular cells or The renal tubular epithelial caused by injury is a pathophysiological in F. A. et of acute and reperfusion Int. Full Text Full Text PDF PubMed Scopus Google M. M. Renal from pathophysiology to Renal 2015; Google Scholar which is by injury (e.g., mitochondrial A.M. Unwin R.J. The not so “mighty chondrion”: emergence of renal diseases due to mitochondrial dysfunction.Nephron Physiol. 2007; 105: 1-10Crossref PubMed Scopus (97) Google T. A. of mitochondrial membrane in proximal tubules after J Physiol Renal Physiol. PubMed Scopus Google Scholar, M. et role of mitochondria in PubMed Scopus Google Scholar, The role of mitochondria in injury in Int. Full Text Full Text PDF PubMed Scopus Google Scholar the acute hours after in renal such as of mitochondria was reported in the proximal epithelial C. Q. et of mitochondrial dynamics in acute kidney injury in and 2009; PubMed Scopus Google Scholar, S. Y. et al.Novel therapeutic protects mitochondria renal and and J Physiol Renal Physiol. 2014; 306: PubMed Scopus Google Scholar, N. H. C. et protects against renal dysfunction via Res. PubMed Scopus Google Scholar, H.H. Liu S. Y. et ATP and kidney Am Soc Nephrol. PubMed Scopus Google Scholar with these our rat showed mitochondria in the proximal tubular cells of the the of the which is the to injury. was probably due to dysregulation of the caused by ATP leading to mitochondrial A. D. A. et of mitochondrial J Physiol Physiol. 2007; PubMed Scopus Google Scholar the after hours of reperfusion, the renal uptake of 18F-BCPP-BF was decreased with the slight of the kidney that was decrease in the mitochondrial protein levels of the kidney and of proximal tubular epithelial the decreased 18F-BCPP-BF uptake this early was due to some in the rather than quantitative The is the to reactive oxygen species and in the as in so as to lower the reactive oxygen species thereby pathophysiological S. A. A. of mitochondrial complex I and its role in Biophys Acta. 2016; PubMed Scopus Google Scholar 18F-BCPP-BF its on with S. Nishiyama S. Y. et PET probes for early therapeutic specifically to mitochondrial complex 2019; PubMed Scopus (5) Google Scholar a which binds to the A and with et of the mitochondrial with as to the Biophys Acta. PubMed Scopus Google Scholar it is that the decrease in the the mitochondrial status in the kidney under stress, which be a for the common of disease The 5/6 rat is used to study the of amounts of mitochondrial proteins (e.g., A protein A ATP and and mitochondrial DNA in the renal tissue of rats were reported the disease L. Yuan Q. Xu T. et al.Pioglitazone improves mitochondrial function in the remnant kidney and protects against renal fibrosis in 5/6 nephrectomized rats.Front Pharmacol. 2017; 8: 545Crossref PubMed Scopus (32) Google A. et al.Mitochondrial impairment in the nephrectomy of chronic renal Nephrol. 2013; PubMed Scopus Google Scholar In this study, the renal uptake of 18F-BCPP-BF to decrease in the early of disease the the decrease was with the of the renal Mitochondrial proteins were decreased in the of 5/6 Thus, the decreased renal PET in the early and of 5/6 is caused by the reduced mitochondrial mass tissue due to the of mitochondria-rich renal tubular epithelial cells. are widely to CKD in clinical and In the 5/6 the renal function and as previously the 18F-BCPP-BF uptake in the was in comparison to the the 18F-BCPP-BF uptake of 5/6 and 5/6 showed a with the kidney function of animal and It is that the of the reduced blood and to the renal S. L. P. et of in 1 diabetic patients with diabetic Int. Full Text Full Text PDF PubMed Scopus Google Scholar the of tubular epithelial cells. Thus, it is suggested that the decreased renal 18F-BCPP-BF uptake in the of mitochondria-rich renal tubular epithelial which was with of the kidney our have been on the kidney mitochondrial status in animal models of glomerulonephritis. We demonstrated that the kidney uptake of 18F-BCPP-BF was slightly decreased in the acute the of with glomerular injury. In in the the decrease in the 18F-BCPP-BF uptake more and was accompanied by a reduction of mitochondrial that the tubulointerstitial more in the and that tubular epithelial cells are in the in the 18F-BCPP-BF uptake probably the of tubular epithelial cells rather than glomerular cells. is in with the of tubular epithelial cells in the of the the 18F-BCPP-BF uptake is it is highly that 18F-BCPP-BF uptake by the kidney the volume of healthy tubular epithelial cells with normally functioning that the PET can be a quantitative indicator of tubular injury. In the decreased 18F-BCPP-BF renal uptake in the kidney disease as as we in this study, or dysfunction of the tubular which is by a common and activation of thereby in to the and renal disease et and kidney disease Am Soc Nephrol. 2015; PubMed Scopus Google Scholar dysfunction is on however, has limitations due to the of and variation. kidney which is associated with renal the functional of injured is by C. M. AKI is 2012; 16: PubMed Scopus Google of acute kidney Nephrol. Full Text Full Text PDF PubMed Scopus (73) Google Scholar studies, in and clinical settings, with 18F-BCPP-BF PET be to this can and quantify even the of the functional tubular mass 18F-BCPP-BF possibly be applied in the safety or and on the for for clinical use have not been an of safety to the of 18F-BCPP-BF used in PET not In a of 18F-BCPP-BF with has been and has to be used in several clinical studies, and and diseases in the and A. et of PET for quantification of mitochondrial and function in healthy human Nucl Med. PubMed Scopus Google Scholar the present study a new PET imaging 18F-BCPP-BF to the mitochondrial status in highly quantitative and less and to the understanding of the of mitochondria in the and of kidney possibly leading to of novel or animal studies were in with the for of under the of the and and by the for the and of and the of the and The kidney of rats was after with and One the kidney was on a after the of In the renal was by the renal and with an of the was for rats were not to hours of reperfusion, were to PET were after PET of and were by a rats were 5/6 was by of the and lower of the by The were under by the of and the of and for rats were after 5/6 such that the blood renal of were In the early study, 5/6 and were to PET imaging after 5/6 the study, 5/6 were further an and a In the in was from of the of the and were to PET imaging of after 5/6 were and of for and in our was via the of rats The rats were and were and 1 and after were in for the early study, rats and rats were to PET imaging after the study, rats and rats were to PET imaging after were after PET imaging for and were after PET imaging and in in and were with and and for were in a for in the of were and of protein was a to under reduced Mitochondrial from rat liver tissue was as a mitochondrial protein proteins were to membrane and with or which against complex I complex complex protein complex and complex ATP mitochondrial complex were with and of kidney tissue were with for hours on and with The were with of for with by with of and and in to were with and observed by a electron was a was a 18F-BCPP-BF was by of the as reported N. Nishiyama S. Kanazawa M. et al.Development of novel PET probes, [18F]BCPP-EF, [18F]BCPP-BF, and [11C]BCPP-EM for mitochondrial complex 1 imaging in the living brain.J Labelled Comp Radiopharm. 2013; 56: 553-561Crossref PubMed Scopus (38) Google Scholar The and of 18F-BCPP-BF were and PET signals were a animal PET The of animal was the study a by to in were on a and in the of the PET for 18F-BCPP-BF was rat from the by emission for PET data were by the method with a and the for the as as from to after were were as the in by the of the and was on the obtained a of were on the liver and of the kidney to in as were the The as of between was evaluated by or and for 18F-BCPP-BF were by We and in and and Nishiyama in for their and and for their and not from in the or with

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