Dual radiotracer analysis of cholinergic neuronal changes in prediabetic mouse pancreas.
BACKGROUND
Pancreatic neuronal changes associated with beta cell loss in type 1 diabetes mellitus are complex, involving, in part, parasympathetic mechanisms to compensate for preclinical hyperglycemia. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor has been shown to be a useful marker of cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[(18)F]fluorobenzyltrozamicol ([(18)F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. The compound 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), available in a tritiated form, binds to M3 muscarinic receptors on beta cells and is a potential target for assessing pancreatic beta cell mass. In this study, we investigate the feasibility of dual radiotracer analysis in identifying neurofunctional changes that may signify type 1 diabetes mellitus in its early preclinical state.


METHODS
Ex vivo determinations of pancreatic uptake were performed in prediabetic nonobese diabetic mice and controls after intravenous injection of [(18)F]FBT or 4-[(3)H]DAMP. Beta cell loss in prediabetic mice was confirmed using immunohistochemical methods.


RESULTS
[(18)F]FBT uptake was significantly higher in prediabetic pancreata than controls: 3.22 +/- 0.81 and 2.51 +/- 1.04, respectively (P < 0.03). 4-[(3)H]DAMP uptake was significantly lower in prediabetic pancreata than controls: 0.612 +/- 0.161 and 0.968 +/- 0.364, respectively (P = 0.01).


CONCLUSIONS
These data suggest that a combination of radiotracer imaging agents that bind to neuronal elements intimately involved in insulin production may be an effective method of evaluating changes associated with early beta cell loss using PET.
Department of Radiology/Nuclear Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA. pbclark@wfubmc.edu
Paige B
PB
Clark
Michael J
MJ
Plaza
Jonathan
J
Kraas
Nicole
N
Burbank
Allen W
AW
Elster
Pradeep
P
Garg
Sudha
S
Garg
H Donald
HD
Gage
Jorge
J
Calles-Escandon
Janice D
JD
Wagner
Kathryn
K
Morton
D000818:Animals; D005462:Fluorine Radioisotopes; D005464:Fluorobenzenes / Q000493:pharmacokinetics; D050417:Insulin-Secreting Cells / Q000000981:diagnostic imaging / Q000473:pathology*; D051379:Mice; D010179:Pancreas / Q000000981:diagnostic imaging / Q000473:pathology*; D010276:Parasympatholytics / Q000493:pharmacokinetics; D010880:Piperidines / Q000493:pharmacokinetics; D011236:Prediabetic State / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000473:pathology; D011859:Radiography; D014316:Tritium
D005462:Fluorine Radioisotopes; D005464:Fluorobenzenes; D010276:Parasympatholytics; D010880:Piperidines; D014316:Tritium; C087277:4-fluorobenzyltrozamicol; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium