title: Exendin-4-based radiopharmaceuticals for glucagonlike peptide-1 receptor PET/CT and SPECT/CT.
abstract: Strong overexpression of glucagonlike peptide-1 (GLP-1) receptors in human insulinoma provides an attractive target for imaging. The first clinical trials demonstrated that GLP-1 receptor SPECT/CT using [Lys(40)(Ahx [6-aminohexanoic acid]-DOTA-(111)In)NH(2)]-exendin-4 can localize hardly detectable insulinomas. However, [Lys(40)(Ahx-DOTA-(111)In)NH(2)]-exendin-4 imaging has drawbacks related to the use of (111)In in that it is costly and carries a relatively high radiation burden for the patient. The aim of this study was the preclinical evaluation of [Lys(40)(Ahx-DOTA-(68)Ga)NH(2)]-exendin-4 for PET/CT and [Lys(40)(Ahx-hydrazinonicotinamide [HYNIC]-(99m)Tc)NH(2)]-exendin-4 for SPECT/CT.
  
  
  METHODS
  Internalization, biodistribution, dosimetry, and imaging studies were performed in the Rip1Tag2 mouse model of pancreatic beta-cell carcinogenesis and compared with our gold standard [Lys(40)(Ahx-DOTA-(111)In)NH(2)]-exendin-4. Poly-glutamic acid and Gelofusine, a gelatin-based plasma expander, were used for renal uptake reduction studies.
  
  
  RESULTS
  The tumor uptake of [Lys(40)(Ahx-DOTA-(68)Ga)NH(2)]-exendin-4 was 205 +/- 59 percentage injected activity per gram of tissue at 4 h. Other GLP-1 receptor-positive organs showed more than 4.8 times lower radioactivity uptake. [Lys(40)(Ahx-HYNIC-(99m)Tc/ethylenediaminediacetic acid [EDDA])NH(2)]-exendin-4, compared with its (111)In- and (68)Ga-labeled sister compounds, showed significantly less tumor and organ uptake. The significantly lower tumor and organ uptake of [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4 did not result in inferior tumor-to-organ ratios or reduced image quality. All radiopeptides tested showed a high tumor-to-background ratio, resulting in the visualization of small tumors (maximum diameter between 1.0 and 3.2 mm) by SPECT and PET. The only exception was the kidneys, which also showed high uptake. This uptake could be reduced by 49%-78% using poly-glutamic acid, Gelofusine, or a combination of the 2. The estimated effective radiation dose was 3.7 muSv/MBq for [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4, which was 8 times less than that for [Lys(40)(Ahx-DOTA-(68)Ga)NH(2)]-exendin-4 and 43 times less than that for [Lys(40)(Ahx-DOTA-(111)In)NH(2)]-exendin-4.
  
  
  CONCLUSIONS
  These promising pharmacokinetic and imaging data show that [Lys(40)(Ahx-DOTA-(68)Ga)NH(2)]-exendin-4 and [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4 are suitable candidates for clinical GLP-1 receptor imaging studies.
authors.affiliation: Clinic and Institute of Nuclear Medicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Damian
authors.initials: D
authors.lastname: Wild
authors.forename: Andreas
authors.initials: A
authors.lastname: Wicki
authors.forename: Rosalba
authors.initials: R
authors.lastname: Mansi
authors.forename: Martin
authors.initials: M
authors.lastname: Béhé
authors.forename: Boris
authors.initials: B
authors.lastname: Keil
authors.forename: Peter
authors.initials: P
authors.lastname: Bernhardt
authors.forename: Gerhard
authors.initials: G
authors.lastname: Christofori
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ell
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Mäcke
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D000077270:Exenatide; D005260:Female; D005710:Gallium Radioisotopes; D000067757:Glucagon-Like Peptide-1 Receptor; D007202:Indicators and Reagents; D007205:Indium Radioisotopes; D007553:Isotope Labeling; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry; D018027:Receptors, Glucagon / Q000378:metabolism*; D017556:Technetium Compounds; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D015899:Tomography, Emission-Computed, Single-Photon; D014688:Venoms / Q000737:chemistry
chemical_list: C000593833:GLP1R protein, human; D005710:Gallium Radioisotopes; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007202:Indicators and Reagents; D007205:Indium Radioisotopes; D010455:Peptides; D019275:Radiopharmaceuticals; D018027:Receptors, Glucagon; D017556:Technetium Compounds; D014688:Venoms; D000077270:Exenatide