title: Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands.
abstract: We combined multimodal imaging (bioluminescence, X-ray computed tomography, and PET), tomographic reconstruction of bioluminescent sources, and two unique, complementary models to evaluate three previously synthesized PET radiotracers thought to target pancreatic beta cells. The three radiotracers {[(18)F]fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]FP-DTBZ), [(18)F](+)-2-oxiranyl-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline ((18)F-AV-266), and (2S,3R,11bR)-9-(3-fluoropropoxy)-2-(hydroxymethyl)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol ((18)F-AV-300)} bind vesicular monoamine transporter 2. Tomographic reconstruction of the bioluminescent signal in mice expressing luciferase only in pancreatic beta cells was used to delineate the pancreas and was coregistered with PET and X-ray computed tomography images. This strategy enabled unambiguous identification of the pancreas on PET images, permitting accurate quantification of the pancreatic PET signal. We show here that, after conditional, specific, and rapid mouse beta-cell ablation, beta-cell loss was detected by bioluminescence imaging but not by PET imaging, given that the pancreatic signal provided by three PET radiotracers was not altered. To determine whether these ligands bound human beta cells in vivo, we imaged mice transplanted with luciferase-expressing human islets. The human islets were imaged by bioluminescence but not with the PET ligands, indicating that these vesicular monoamine transporter 2-directed ligands did not specifically bind beta cells. These data demonstrate the utility of coregistered multimodal imaging as a platform for evaluation and validation of candidate ligands for imaging islets.
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: John
authors.initials: J
authors.lastname: Virostko
authors.forename: Joseph
authors.initials: J
authors.lastname: Henske
authors.forename: Laurent
authors.initials: L
authors.lastname: Vinet
authors.forename: Smaragda
authors.initials: S
authors.lastname: Lamprianou
authors.forename: Chunhua
authors.initials: C
authors.lastname: Dai
authors.forename: Aramandla
authors.initials: A
authors.lastname: Radhika
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Baldwin
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Ansari
authors.forename: Franz
authors.initials: F
authors.lastname: Hefti
authors.forename: Daniel
authors.initials: D
authors.lastname: Skovronsky
authors.forename: Hank F
authors.initials: HF
authors.lastname: Kung
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.forename: Todd E
authors.initials: TE
authors.lastname: Peterson
authors.forename: Paolo
authors.initials: P
authors.lastname: Meda
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000473:pathology; D007515:Islets of Langerhans / Q000378:metabolism; D008024:Ligands; D049449:Luminescence; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed / Q000379:methods*
chemical_list: D007328:Insulin; D008024:Ligands