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.diabetes | insulin | molecular imaging | pancreatic islet | bioluminescence tomography

Reporter islets in the eye reveal the plasticity of the endocrine pancreas

“…Ex vivo imaging techniques involve the imaging of exteriorized pancreas by confocal microscopy (26) or optical coherence microscopy (27). Finally, several noninvasive in vivo imaging techniques aim to longitudinally quantify total beta cell mass, including magnetic resonance imaging (28), positron emission tomography (29), bioluminescence imaging (30), and combined multimodal imaging (31). All of these techniques deliver precious information either at the islet population level or at the islet and cellular level.…”

Implanted islets in the anterior chamber of the eye are prone to autoimmune attack in a mouse model of diabetes

“…Recently, various imaging techniques for evaluating the fate of transplanted islets and the progression of autoimmune diabetes have been examined [5,[7][8][9][10][11][12]. Among these, optical imaging provides an attractive imaging modality because it is a non-invasive and non-ionising technique [13] and can track live cells in vivo by fluorescent or bioluminescent labelling.…”

“…Fluorescent imaging is hampered by two major limitations: insufficient penetration depth of most fluorescent agents and inadequate resolution resulting from the high absorption and broad autofluorescence of tissues [13]. Even using near-infrared contrast agents or tissue-specific bioluminescence [10][11][12], these techniques are not able to attain single-cell-level sensitivity [14]. The anterior chamber of the eye has been a popular transplantation site for decades [15], as transplanted tissue is readily vascularised and innervated by the iris [16] and the graft can be visualised noninvasively.…”

A new view of the beta cell

“…However, recent multimodal imaging has provided strong evidence that this approach may have limited use for beta cell imaging because the PET signal generated does not correlate with beta cell mass [8]. In their paper [8] the authors stipulate important directions for future preclinical evaluations of beta cell probes.…”

“…DTBZ is used clinically for positron emission tomography (PET) imaging of dopaminergic neurons in the central nervous system and is the only tracer currently being clinical trialled for beta cell imaging by PET [7]. However, recent multimodal imaging has provided strong evidence that this approach may have limited use for beta cell imaging because the PET signal generated does not correlate with beta cell mass [8]. In their paper [8] the authors stipulate important directions for future preclinical evaluations of beta cell probes.…”