DOTA derivative

Guideline for PET/CT imaging of neuroendocrine neoplasms with 68Ga-DOTA-conjugated somatostatin receptor targeting peptides and 18F-DOPA

Purpose & methods: Neuroendocrine neoplasms are a heterogenous group of tumours, for which nuclear medicine plays an important role in the diagnostic work-up as well as in the targeted therapeutic options. This guideline is aimed to assist nuclear medicine physicians in recommending, performing, reporting and interpreting the results of somatostatin receptor (SSTR) PET/CT imaging using 68Ga-DOTA-conjugated peptides, as well as 18F-DOPA imaging for various neuroendocrine neoplasms. Results & conclusion: The previous procedural guideline by EANM regarding the use PET/CT tumour imaging with 68Ga-conjugated peptides has been revised and updated with the relevant and recent literature in the field with contribution of distinguished experts.

68Ga-DOTA-peptides in the diagnosis of NET

(68)Ga-DOTA-peptides are increasingly used for the detection of neuroendocrine tumors (NET) in clinical trials in Europe. They have been proved accurate for the detection of NET lesions (at primary and metastatic sites) and no adverse effects were recorded. Moreover, providing data on somatostatin receptors expression on NET cells, (68)Ga-DOTA-peptides PET/CT is becoming a fundamental procedure to be performed before starting therapy and to guide treatment with either hot or cold somatostatin analogues. The easy and economic synthesis process is another advantage that is supporting its clinical use even in centers without an on-site cyclotron.

Single-armed phenylsulfonated pyridine derivative of DOTA is rigid and stable paramagnetic tag in protein analysis

Single-armed DOTA-like phenylsulfonated pyridine derivatives are rigid and stable paramagnetic tags for site-specific labeling of proteins. Their reactions with a solvent-exposed protein thiol group generate a stable C-S bond and produce one single paramagnetic species in solution NMR. The generated large paramagnetic effects yield valuable long-range structural restraints for proteins.

Synthesis and evaluation of a para-carboxylated benzyl-DOTA for labeling peptides and polypeptides

Introduction: Radiolabeled peptides and low-molecular-weight (LMW) polypeptides show high and persistent radioactivity levels in the kidney. To develop a DOTA-based bifunctional chelating agent that provides a radiometabolite with a rapid elimination rate from the kidney, a para-carboxyl Bn-DOTA (p-COOH-Bn-DOTA) was designed, synthesized, and evaluated.
Methods: A precursor compound, p-COOH-Bn-DOTA(^tBu)₄, was synthesized in 9 steps using N-Boc-p-iodo-L-phenylalanine as the starting material. A synthetic somatostatin analog (TOC) was used as a representative peptide metabolized in the renal lysosomes. p-COOH-Bn-DOTA-conjugated TOC (DOTA-Bn-TOC) was synthesized by the conventional solid-phase peptide synthesis using p-COOH-Bn-DOTA(^tBu)₄. DOTA-tris(^tBu ester) was also conjugated with TOC to prepare DOTATOC. ¹¹¹In-labeling of the peptides was conducted under similar conditions. The radiochemical conversions, stability against apo-transferrin (apoTf), and in vivo behaviors were compared.
Results: [¹¹¹In]In-DOTA-Bn-TOC was obtained with higher radiochemical conversions than [¹¹¹In]In-DOTATOC. Both ¹¹¹In-labeled TOC derivatives remained stable against apoTf. In biodistribution studies, [¹¹¹In]In-DOTA-Bn-TOC exhibited higher initial uptake in the kidney, followed by a faster elimination rate of radioactivity into the urine than [¹¹¹In]In-DOTATOC. The metabolic studies showed that the shorter residence time of the radiometabolite from [¹¹¹In]In-DOTA-Bn-TOC was responsible for the renal radioactivity decline.
Conclusion: p-COOH-Bn-DOTA provides stable ¹¹¹In-labeled peptides in high yields at low peptide concentrations. p-COOH-Bn-DOTA also provides a radiometabolite with a short residence time in the kidney. Such characteristics would render p-COOH-Bn-DOTA useful to the future application to radiolabeled LMW polypeptides with low renal radioactivity levels.

The ubiquitous DOTA and its derivatives: the impact of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid on biomedical imaging

Over the last twenty-five years 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) has made a significant impact on the field of diagnostic imaging. DOTA is not the only metal chelate in use in medical diagnostics, but it is the only one to significantly impact on all of the major imaging modalities Magnetic Resonance (MR), Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), and Fluorescence imaging. This crossover of modalities has been possible due to the versatility of DOTA firstly, to complex a variety of metal ions and secondly, the ease with which it can be modified for different disease states. This has driven research over the last two decades into the chemistry of DOTA and the modification of the substituent pendant arms of this macrocycle to create functional, targeted and dual-modal imaging agents. The primary use of DOTA has been with the lanthanide series of metals, gadolinium for MRI, europium and terbium for fluorescence and neodymium for near infra-red imaging. There are now many research groups dedicated to the use of lanthanides with DOTA although other chelates such as DTPA and NOTA are being increasingly employed. The ease with which DOTA can be conjugated to peptides has given rise to targeted imaging agents seen in the PET, SPECT and radiotherapy fields. These modalities use a variety of radiometals that complex with DOTA, e.g.(64)Cu and (68)Ga which are used in clinical PET scans, (111)In, and (90)Y for SPECT and radiotherapy. In this article, we will demonstrate the remarkable versatility of DOTA, how it has crossed the imaging modality boundaries and how it has been successfully transferred into the clinic.