Original Articles
Demonstration of [11C] 5-hydroxy-L-tryptophan uptake and decarboxylation in carcinoid tumors by specific positioning labeling in positron emission tomography

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Abstract

In three patients with carcinoid liver and/or lymph node metastases, we studied the process of tumor tracer uptake and decarboxylation by means of positron emission tomography (PET) using 5-hydroxy-L-tryptophan (5-HTP) 11C-labeled in the β-position (HTP) and later the same day with 5-HTP 11C-labeled in the carboxyl group (HTC). With HTP, in which the 11C-label follows the molecule through decarboxylation to form 11C-serotonin, a high tumor accumulation of the tracer was found. With HTC, in which the label is rapidly eliminated from the tissues as 11CO2 if decarboxylation takes place, there was virtually no uptake by the tumors. By utilizing data from PET scanning with both tracers, we could quantify the decarboxylation rate and tissue accumulation of [11C]-serotonin and hence the enzymatic action of aromatic amino acid decarboxylase.

Introduction

The carcinoid tumors belong to the so-called APUDomas, a group of tumors characterized by their capacity for amine precursor uptake and decarboxylation 29, 30. Thus, amine precursors such as 5-hydroxy-L-tryptophan (5-HTP) and L-dihydroxyphenylalanine (L-DOPA) may be taken up by the tumor cells and, through the action of aromatic amino acid decarboxylase (AADC), these precursors become decarboxylated and convert to the amines serotonin and dopamine, respectively. The resulting amines are then stored in secretory granulae within the cytoplasm. Within the APUDoma group of tumors, the carcinoids, together with the endocrine pancreatic tumors (e.g., gastrinomas, insulinomas, glucagonomas) constitute the so-called neuroendocrine gastrointestinal tumors.

Thus, in carcinoid tumors, and especially in those of mid-gut origin, serotonin is produced via the precursor tryptophan and 5-HTP. The circulating serotonin is then further metabolized to 5-hydroxyindole acetic acid (5-HIAA), which is excreted in the urine and constitutes an important tumor marker in these patients. Based on this biochemical pathway, 11C-labeled 5-HTP and L-DOPA have been synthesized 5, 6 and used as tracers for positron emission tomography (PET) imaging of neuroendocrine gastrointestinal tumors 1, 11, 27. The high tracer accumulation in tumors compared with that in normal tissues allows improved visualization by PET compared with conventional morphologic imaging modalities such as computed tomography (CT) 11, 27. Exceptions are small insulinomas and so-called nonfunctioning endocrine pancreatic tumors. In addition, an indication of the tumor’s metabolic status can be obtained, as expressed in amine precursor accumulation. For example, in some patients where extensive replacement of the liver by tumor was diagnosed by CT, PET could demonstrate that many of these metastases were metabolically inactive, possibly constituting necrotic or fibrotic tissue.

In addition to imaging for radiologic diagnosis, PET is generally accepted as a refined tool that is capable of demonstrating biochemical processes in vivo. A principal limitation of the technique, however, is the fact that the radioactivity concentration quantified in the image merely reflects the tissue accumulation of the radioactive label, irrespective of the molecule to which it is attached. Therefore, in a single-tracer PET study it is usually impossible to determine the fate of the tracer molecule over time. The label may remain attached to the originally injected tracer, follow a metabolite, or enter a synthetic pathway and be incorporated into a new compound. The proportions of the resulting various labeled molecules at the different time points following tracer injection usually escape evaluation as well.

A previous double-tracer study (3) performed with 11C-L-DOPA labeled in the β-position and in the carboxyl group, respectively, allowed in vivo demonstration of the decarboxylation by AADC to dopamine in endocrine pancreatic tumors. In the present work we wanted to demonstrate that the same process occurs in carcinoid tumors. Therefore, PET was performed repeatedly in carcinoid patients by means of 11C-labeled 5-HTP where the 11C atom was selectively positioned to either follow the bulk of the molecule in its conversion to [11C]-serotonin (labeling in the β-position [HTP]) or positioned in the carboxyl group (labeling in the carboxy position [HTC]) and consequently being split off as 11CO2. Because of these differences in the pharmacokinetics of the β- and carboxy position labeled 5-HTP, the decarboxylation rate in the carcinoid metastases could be illustrated and estimated by using PET.

Section snippets

Patients

Patient 1, a 62-year-old male, was admitted to the Department of Internal Medicine with the carcinoid syndrome. He was shown by CT and ultrasound (US) to have multiple liver metastases. At histopathology following US-guided tru-cut biopsy, these were found to be of mid-gut origin. U-HIAA was elevated (395 μmol/ 24 h; reference value < 80 μmol/24 h) as was plasma chromogranin A (5,200 μg/L; reference value < 350 μg/L). Medical treatment was started with daily subcutaneous injections of

Tumor and normal tissue accumulation

Quantitative PET data for tumors and for various normal tissues during PET using HTP are shown in TABLE 1, TABLE 2. For the SUV calculation, image data was obtained from 15 to 45 min after tracer injection were used. A high tracer accumulation was generally demonstrated in the carcinoid metastases (Fig. 4A ), especially in the liver metastasis in patient 1 and in the majority of the lymph node metastases in patient 3. In tumor tissue (N = 12) the mean SUV was 15.0 (range 6.3–31.6), SUVhs 17.9

Discussion

Consistent with previous results 11, 27, a high tumor tissue accumulation of β-position labeled 11C-HTP was found, corresponding to the morphologic findings by CT. As expected, the metastases were more easily depicted by PET than by CT, which held true for both liver metastases and lymph node metastases. By way of illustration, in patient 2 more liver metastases were found by PET than by CT and in patient 3 an additional retrocrural lymph node metastasis was detected by PET (data not shown).

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    Supported by the Swedish Cancer Society.

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