Abstract
Purpose
Previous studies demonstrated the utility of [18F]fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ) as a positron emission tomography (PET) radiotracer for the vesicular monoamine transporter type 2 (VMAT2) to quantify beta cell mass in healthy control (HC) and type 1 diabetes mellitus (T1DM) groups. Quantification of specific binding requires measurement of non-displaceable uptake. Our goal was to identify a reference tissue (renal cortex or spleen) to quantify pancreatic non-specific binding of [18F]FP-(+)-DTBZ with the inactive enantiomer, [18F]FP-(−)-DTBZ. This was the first human study of [18F]FP-(−)-DTBZ.
Procedures
Six HCs and four T1DM patients were scanned on separate days after injection of [18F]FP-(+)-DTBZ or [18F]FP-(−)-DTBZ. Distribution volumes (VT) and standardized uptake values (SUVs) were compared between groups. Three methods for calculation of non-displaceable uptake (VND) or reference SUV were applied: (1) use of [18F]FP-(+)-DTBZ reference VT as VND, assuming VND is uniform across organs; (2) use of [18F]FP-(−)-DTBZ pancreatic VT as VND, assuming that VND is uniform between enantiomers in the pancreas; and (3) use of a scaled [18F]FP-(+)-DTBZ reference VT as VND, assuming that a ratio of non-displaceable uptake between organs is uniform between enantiomers. Group differences in VT (or SUV), binding potential (BPND), or SUV ratio (SUVR) were estimated using these three methods.
Results
[18F]FP-(−)-DTBZ VT values were different among organs, and VT(+) and VT(−) were also different in the renal cortex and spleen. Method 3 with the spleen to estimate VND (or reference SUV) gave the highest non-displaceable uptake and the largest HC vs. T1DM group differences. Significant group differences were also observed in VT (or SUV) with method 1 using spleen. SUV was affected by differences in the input function between groups and between enantiomers.
Conclusions
Non-displaceable uptake was different among organs and between enantiomers. Use of scaled spleen VT values for VND is a suitable method for quantification of VMAT2 in the pancreas.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Anlauf M, Eissele R, Schafer MK et al (2003) Expression of the two isoforms of the vesicular monoamine transporter (VMAT1 and VMAT2) in the endocrine pancreas and pancreatic endocrine tumors. J Histochem Cytochem 51(8):1027–1040. https://doi.org/10.1177/002215540305100806
Harris PE, Ferrara C, Barba P, Polito T, Freeby M, Maffei A (2008) VMAT2 gene expression and function as it applies to imaging beta-cell mass. J Mol Med (Berl) 86(1):5–16. https://doi.org/10.1007/s00109-007-0242-x
Maffei A, Liu Z, Witkowski P, Moschella F, Pozzo GD, Liu E, Herold K, Winchester RJ, Hardy MA, Harris PE (2004) Identification of tissue-restricted transcripts in human islets. Endocrinology 145(10):4513–4521. https://doi.org/10.1210/en.2004-0691
Saisho Y, Harris PE, Butler AE, Galasso R, Gurlo T, Rizza RA, Butler PC (2008) Relationship between pancreatic vesicular monoamine transporter 2 (VMAT2) and insulin expression in human pancreas. J Mol Histol 39(5):543–551. https://doi.org/10.1007/s10735-008-9195-9
Naganawa M, Lin SF, Lim K, Labaree D, Ropchan J, Harris P, Huang Y, Ichise M, Carson RE, Cline GW (2016) Evaluation of pancreatic VMAT2 binding with active and inactive enantiomers of 18F-FP-DTBZ in baboons. Nucl Med Biol 43(12):743–751. https://doi.org/10.1016/j.nucmedbio.2016.08.018
Rahier J, Goebbels RM, Henquin JC (1983) Cellular composition of the human diabetic pancreas. Diabetologia 24(5):366–371
Kung MP, Hou C, Lieberman BP, Oya S, Ponde DE, Blankemeyer E, Skovronsky D, Kilbourn MR, Kung HF (2008) In vivo imaging of beta-cell mass in rats using 18F-FP-(+)-DTBZ: a potential PET ligand for studying diabetes mellitus. J Nucl Med 49(7):1171–1176. https://doi.org/10.2967/jnumed.108.051680
Harris PE, Farwell MD, Ichise M (2013) PET quantification of pancreatic VMAT 2 binding using (+) and (-) enantiomers of [18F]FP-DTBZ in baboons. Nucl Med Biol 40(1):60–64. https://doi.org/10.1016/j.nucmedbio.2012.09.003
Normandin MD, Petersen KF, Ding YS, Lin SF, Naik S, Fowles K, Skovronsky DM, Herold KC, McCarthy TJ, Calle RA, Carson RE, Treadway JL, Cline GW (2012) In vivo imaging of endogenous pancreatic beta-cell mass in healthy and type 1 diabetic subjects using F-18-fluoropropyl-dihydrotetrabenazine and PET. J Nucl Med 53(6):908–916. https://doi.org/10.2967/jnumed.111.100545
Freeby MJ, Kringas P, Goland RS, Leibel RL, Maffei A, Divgi C, Ichise M, Harris PE (2016) Cross-sectional and test-retest characterization of PET with [18F]FP-(+)-DTBZ for beta cell mass estimates in diabetes. Mol Imaging Biol 18(2):292–301. https://doi.org/10.1007/s11307-015-0888-7
Singhal T, Ding YS, Weinzimmer D, Normandin MD, Labaree D, Ropchan J, Nabulsi N, Lin SF, Skaddan MB, Soeller WC, Huang Y, Carson RE, Treadway JL, Cline GW (2011) Pancreatic beta cell mass PET imaging and quantification with [11C]DTBZ and [18F]FP-(+)-DTBZ in rodent models of diabetes. Mol Imaging Biol 13(5):973–984. https://doi.org/10.1007/s11307-010-0406-x
Kung MP, Hou C, Goswami R, Ponde DE, Kilbourn MR, Kung HF (2007) Characterization of optically resolved 9-fluoropropyl-dihydrotetrabenazine as a potential PET imaging agent targeting vesicular monoamine transporters. Nucl Med Biol 34(3):239–246. https://doi.org/10.1016/j.nucmedbio.2006.12.005
Watabe H, Endres CJ, Breier A, Schmall B, Eckelman WC, Carson RE (2000) Measurement of dopamine release with continuous infusion of [11C]raclopride: optimization and signal-to-noise considerations. J Nucl Med 41(3):522–530
Pavlidis T (1982) Algorithms for graphics and image processing. Computer Science, DOI: https://doi.org/10.1007/978-3-642-93208-3
Ichise M, Toyama H, Innis RB, Carson RE (2002) Strategies to improve neuroreceptor parameter estimation by linear regression analysis. J Cereb Blood Flow Metab 22(10):1271–1281. https://doi.org/10.1097/01.WCB.0000038000.34930.4E
Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, Carson RE (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27(9):1533–1539. https://doi.org/10.1038/sj.jcbfm.9600493
Arikawa S, Uchida M, Kunou Y, Kaida H, Uozumi J, Hayabuchi N, Okabe Y, Murotani K (2012) Assessment of chronic pancreatitis: use of whole pancreas perfusion with 256-slice computed tomography. Pancreas 41(4):535–540. https://doi.org/10.1097/MPA.0b013e3182374fe0
Anderson H, Yap JT, Wells P, Miller MP, Propper D, Price P, Harris AL (2003) Measurement of renal tumour and normal tissue perfusion using positron emission tomography in a phase II clinical trial of razoxane. Br J Cancer 89(2):262–267. https://doi.org/10.1038/sj.bjc.6601105
Koeppe RA, Frey KA, Kuhl DE, Kilbourn MR (1999) Assessment of extrastriatal vesicular monoamine transporter binding site density using stereoisomers of [11C]dihydrotetrabenazine. J Cereb Blood Flow Metab 19(12):1376–1384. https://doi.org/10.1097/00004647-199912000-00011
Tsao HH, Skovronsky DM, Lin KJ, Yen TC, Wey SP, Kung MP (2011) Sigma receptor binding of tetrabenazine series tracers targeting VMAT2 in rat pancreas. Nucl Med Biol 38(7):1029–1034. https://doi.org/10.1016/j.nucmedbio.2011.03.006
Goland R, Freeby M, Parsey R, Saisho Y, Kumar D, Simpson N, Hirsch J, Prince M, Maffei A, Mann JJ, Butler PC, van Heertum R, Leibel RL, Ichise M, Harris PE (2009) 11C-dihydrotetrabenazine PET of the pancreas in subjects with long-standing type 1 diabetes and in healthy controls. J Nucl Med 50(3):382–389. https://doi.org/10.2967/jnumed.108.054866
Virostko J, Hilmes M, Eitel K, Moore DJ, Powers AC (2016) Use of the electronic medical record to assess pancreas size in type 1 diabetes. PLoS One 11(7):e0158825. https://doi.org/10.1371/journal.pone.0158825
Acknowledgements
The authors appreciate the excellent technical assistance of the staff at the Yale University PET Center.
Funding
This study was sponsored by the Juvenile Diabetes Research Foundation 37-2011-633. This work was also made possible by 1S10OD010322-01 and by CTSA Grant Number UL1 TR000142 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Ethical Approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Yale University Human Investigation Committee and the Yale-New Haven Hospital Radiation Safety Committee.
Informed Consent
Informed consent was obtained from all patients included in this study.
Electronic supplementary material
ESM 1
(PDF 840 kb)
Rights and permissions
About this article
Cite this article
Naganawa, M., Lim, K., Nabulsi, N.B. et al. Evaluation of Pancreatic VMAT2 Binding with Active and Inactive Enantiomers of [18F]FP-DTBZ in Healthy Subjects and Patients with Type 1 Diabetes. Mol Imaging Biol 20, 835–845 (2018). https://doi.org/10.1007/s11307-018-1170-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11307-018-1170-6