Evaluation of pancreatic VMAT2 binding with active and inactive enantiomers of18F-FP-DTBZ in baboons.
BACKGROUND
18F-Fluoropropyl-(+)-dihydrotetrabenazine (18F-FP-(+)-DTBZ) is a vesicular monoamine transporter type 2 (VMAT2) radiotracer for positron emission tomography (PET) imaging to quantify human β-cell mass. Renal cortex and spleen have been suggested as reference regions, however, little is known about18F-FP-(+)-DTBZ binding in these regions including the fraction of radiometabolite. We compared the kinetics of18F-FP-(+)-DTBZ and its inactive enantiomer18F-FP-(-)-DTBZ in baboons, estimated the non-displaceable binding (VND) of the tracers, and used ex vivo studies to measure radiometabolite fractions.


METHODS
PET scans were conducted for up to 4h with (+) and (-) enantiomers. Displacement experiments using unlabeled (+) and (-) enantiomers of FP-DTBZ and fluvoxamine (to evaluate sigma-1 receptor binding) were performed. SUV curves were used to calculate displacement values in the pancreas, renal cortex, and spleen. Distribution volumes (VT) were computed, and three approaches for calculation of VNDwere compared: (1)18F-FP-(+)-DTBZ reference VT, (2)18F-FP-(-)-DTBZ pancreatic VT, and (3) a scaled18F-FP-(+)-DTBZ reference VTvalues. Ex vivo study was conducted to measure radiometabolite fraction in homogenized tissue samples from baboons at 90min post-injection.


RESULTS
Spleen uptake was lowest for both tracers. Highest uptake was in the pancreas with18F-FP-(+)-DTBZ and renal cortex with18F-FP-(-)-DTBZ. Substantial displacement effect was observed only with unlabeled FP-(+)-DTBZ in the18F-FP-(+)-DTBZ studies. Radiometabolite fraction was higher in the renal cortex than the spleen. Approaches (1) and (3) with spleen to estimate VNDprovided lowest inter-subject variability of BPND.


CONCLUSIONS
VTdifferences among organs and between enantiomers indicated that scaling of reference region values is needed for quantification of VMAT2 binding in the pancreas with18F-FP-(+)-DTBZ. Since the kidney PET signal has greater partial volume averaging and more radiometabolites, the spleen was considered a more practical candidate for use as a scaled-reference region in the quantification of18F-FP-(+)-DTBZ in the pancreas.
Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT, United States, 06520.
Mika
M
Naganawa
Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT, United States, 06520.
Shu-Fei
SF
Lin
Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT, United States, 06520.
Keunpoong
K
Lim
Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT, United States, 06520.
David
D
Labaree
Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT, United States, 06520.
Jim
J
Ropchan
Columbia University, New York, NY, United States.
Paul
P
Harris
Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT, United States, 06520.
Yiyun
Y
Huang
Columbia University, New York, NY, United States.
Masanori
M
Ichise
Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT, United States, 06520.
Richard E
RE
Carson
Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT, United States, 06520.
Gary W
GW
Cline
D000818:Animals; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D010179:Pancreas / Q000378:metabolism*; D010215:Papio; D011485:Protein Binding; D013237:Stereoisomerism; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D005462:Fluorine Radioisotopes; D050493:Vesicular Monoamine Transport Proteins; C549477:florbenazine F 18; D013747:Tetrabenazine
(18)F-FP-(+)-DTBZ; (18)F-FP-(−)-DTBZ; PET; Pancreas non-displaceable binding; Vesicular monoamine transporter type 2; β-cell mass
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