Preclinical Comparative Study of ⁶⁸Ga-Labeled DOTA, NOTA, and HBED-CC Chelated Radiotracers for Targeting PSMA

⁶⁸Ga-labeled, low-molecular-weight imaging agents that target the prostate-specific membrane antigen (PSMA) are increasingly used clinically to detect prostate and other cancers with positron emission tomography (PET). The goal of this study was to compare the pharmacokinetics of three PSMA-targeted radiotracers: ^<b>68</b><b>Ga-1</b>, using DOTA-monoamide as the chelating agent; ^<b>68</b><b>Ga-2</b>, containing the macrocyclic chelating agent <i>p</i>-SCN-Bn-NOTA; and ⁶⁸Ga-DKFZ-PSMA-11, currently in clinical trials, which uses the acyclic chelating agent, HBED-CC. The PSMA-targeting scaffold for all three agents utilized a similar Glu-urea-Lys-linker construct. Each radiotracer enabled visualization of PSMA+ PC3 PIP tumor, kidney, and urinary bladder as early as 15 min post-injection using small animal PET/computed tomography (PET/CT). ^<b>68</b><b>Ga-2</b> demonstrated the fastest rate of clearance from all tissues in this series and displayed higher uptake in PSMA+ PC3 PIP tumor compared to ^<b>68</b><b>Ga-1</b> at 1 h post-injection. There was no significant difference in PSMA+ PC3 PIP tumor uptake for the three agents at 2 and 3 h post-injection. ⁶⁸Ga-DKFZ-PSMA-11 demonstrated the highest uptake and retention in normal tissues, including kidney, blood, spleen, and salivary glands and PSMA-negative PC3 flu tumors up to 3 h post-injection. In this preclinical evaluation ^<b>68</b><b>Ga-2</b> had the most advantageous characteristics for PSMA-targeted PET imaging

Effect of Chelators on the Pharmacokinetics of ^99mTc-Labeled Imaging Agents for the Prostate-Specific Membrane Antigen (PSMA)

Technetium-99m, the most commonly used radionuclide in nuclear medicine, can be attached to biologically important molecules through a variety of chelating agents, the choice of which depends upon the imaging application. The prostate-specific membrane antigen (PSMA) is increasingly recognized as an important target for imaging and therapy of prostate cancer (PCa). Three different ^99mTc-labeling methods were employed to investigate the effect of the chelator on the biodistribution and PCa tumor uptake profiles of 12 new urea-based PSMA-targeted radiotracers. This series includes hydrophilic ligands for radiolabeling with the [^99mTc­(CO)₃]⁺ core (<b>L8</b>–<b>L10</b>), traditional N_<i>x</i>S_<i>y</i>-based chelating agents with varying charge and polarity for the ^99mTc-oxo core (<b>L11</b>–<b>L18</b>), and a ^99mTc-organohydrazine-labeled radioligand (<b>L19</b>). ^99mTc­(I)-Tricarbonyl-labeled [^99mTc]<b>L8</b> produced the highest PSMA+ PC3 PIP to PSMA– PC3 flu tumor ratios and demonstrated the lowest retention in normal tissues including kidney after 2 h. These results suggest that choice of chelator is an important pharmacokinetic consideration in the development of ^99mTc-labeled radiopharmaceuticals targeting PSMA

⁶⁴Cu-Labeled Inhibitors of Prostate-Specific Membrane Antigen for PET Imaging of Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a well-recognized target for identification and therapy of a variety of cancers. Here we report five ⁶⁴Cu-labeled inhibitors of PSMA, [⁶⁴Cu]<b>3</b>–<b>7</b>, which are based on the lysine–glutamate urea scaffold and utilize a variety of macrocyclic chelators, namely NOTA­(<b>3</b>), PCTA­(<b>4</b>), Oxo-DO3A­(<b>5</b>), CB-TE2A­(<b>6</b>), and DOTA­(<b>7</b>), in an effort to determine which provides the most suitable pharmacokinetics for in vivo PET imaging. [⁶⁴Cu]<b>3</b>–<b>7</b> were prepared in high radiochemical yield (60–90%) and purity (>95%). Positron emission tomography (PET) imaging studies of [⁶⁴Cu]<b>3</b>–<b>7</b> revealed specific accumulation in PSMA-expressing xenografts (PSMA+ PC3 PIP) relative to isogenic control tumor (PSMA– PC3 flu) and background tissue. The favorable kinetics and high image contrast provided by CB-TE2A chelated [⁶⁴Cu]<b>6</b> suggest it as the most promising among the candidates tested. That could be due to the higher stability of [⁶⁴Cu]­CB-TE2A as compared with [⁶⁴Cu]­NOTA, [⁶⁴Cu]­PCTA, [⁶⁴Cu]­Oxo-DO3A, and [⁶⁴Cu]­DOTA chelates in vivo