Tc-99m-HYNIC-Gastrin Peptides: Assisted Coordination of Tc-99m by Amino Acid Side Chains Results in Improved Performance Both In Vitro and In Vivo

TY - JOUR

T1 - Tc-99m-HYNIC-Gastrin Peptides: Assisted Coordination of Tc-99m by Amino Acid Side Chains Results in Improved Performance Both In Vitro and In Vivo

AU - King, Robert

AU - Surfraz, M. Bashir-Uddin

AU - Finucane, Ciara

AU - Biagini, Stefano C. G.

AU - Blower, Philip J.

AU - Mather, Stephen J.

PY - 2009/4/1

Y1 - 2009/4/1

N2 - The aim of this study was to determine the effects of assisted coordination by amino acids such as histidine and glutamic acid on the function of Tc-99m-labeled gastrin peptide-hydrazinonicotinamide (HYNIC) conjugates and their ability to target cholecystokinin-R in small-animal models. Methods: Three peptide-HYNIC conjugates containing the -AYGWMDF-NH2 C-terminal sequence and combinations of histidine, glutamic acid, and glycine were synthesized, radiolabeled with Tc-99m/Tc-99 using either tricine or ethylenediaminediacetic acid as a coligand, and analyzed by the high-performance liquid chromatography and liquid chromatography-mass spectrometric techniques. Stability, receptor binding, and internalization and in vivo targeting in AR42J-bearing mice were assessed. Results: When radiolabeling was performed using tricine as a coligand, the insertion of a histidine residue near the HYNIC residue resulted in the displacement of one molecule of tricine from the coordination sphere, a reduction in the number of radiolabeled species formed, an improvement in the in vitro stability, an increase in the rate of radiopeptide internalization, and a significant improvement in tumor uptake in vivo. When radiolabeling was performed using ethylenediaminediacetic acid as a coligand, no effect on coligand binding, homogeneity, or in vitro stability was observed but a significant improvement in the internalization in vitro and tumor uptake in vivo was again found. All of the complexes formed showed similar receptor affinity in competitive radioligand binding assays. Conclusion: The insertion of histidine into the sequence of peptide-HYNIC conjugates can result in more stable, more homogeneous complexes that show improvements in tumor-targeting performance both in vitro and in vivo.

AB - The aim of this study was to determine the effects of assisted coordination by amino acids such as histidine and glutamic acid on the function of Tc-99m-labeled gastrin peptide-hydrazinonicotinamide (HYNIC) conjugates and their ability to target cholecystokinin-R in small-animal models. Methods: Three peptide-HYNIC conjugates containing the -AYGWMDF-NH2 C-terminal sequence and combinations of histidine, glutamic acid, and glycine were synthesized, radiolabeled with Tc-99m/Tc-99 using either tricine or ethylenediaminediacetic acid as a coligand, and analyzed by the high-performance liquid chromatography and liquid chromatography-mass spectrometric techniques. Stability, receptor binding, and internalization and in vivo targeting in AR42J-bearing mice were assessed. Results: When radiolabeling was performed using tricine as a coligand, the insertion of a histidine residue near the HYNIC residue resulted in the displacement of one molecule of tricine from the coordination sphere, a reduction in the number of radiolabeled species formed, an improvement in the in vitro stability, an increase in the rate of radiopeptide internalization, and a significant improvement in tumor uptake in vivo. When radiolabeling was performed using ethylenediaminediacetic acid as a coligand, no effect on coligand binding, homogeneity, or in vitro stability was observed but a significant improvement in the internalization in vitro and tumor uptake in vivo was again found. All of the complexes formed showed similar receptor affinity in competitive radioligand binding assays. Conclusion: The insertion of histidine into the sequence of peptide-HYNIC conjugates can result in more stable, more homogeneous complexes that show improvements in tumor-targeting performance both in vitro and in vivo.

U2 - 10.2967/jnumed.108.058289

DO - 10.2967/jnumed.108.058289

M3 - Article

VL - 50

SP - 591

EP - 598

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

IS - 4

ER -