99mTc labelled peptides for imaging of peripheral receptors. Final report of a co-ordinated research project. 1995-1999

99mTc radiopharmaceuticals have remained the workhorse of diagnostic nuclear medicine over the last three decades ever since the introduction of the gamma camera as the main imaging instrument. Due to the near ideal nuclear properties such as gamma energy, half-life, lack of beta radiation and easy availability as a convenient generator system at an affordable cost of 99mTc, it can be reasonably anticipated that 99mTc will continue to retain this position in the foreseeable future. To a large extent this has been possible because of the successful development, over the years, of 99mTc radiopharmaceuticals as substitutes for other clinically well established agents. Examples of these success stories are 99mTc substitutes for 131I hippuran and rose bengal 201Tl and 123I brain perfusion agents, which have come to be known collectively as 'second generation 99mTc radiopharmaceuticals'. It should be acknowledged that each one of these developments was a result of innovative and sustained research and development efforts by scientists from different parts of the world. Concurrently these research efforts have made significant contributions to better understanding of the radiochemistry and co-ordination chemistry of 99mTc. The radiopharmaceutical scientists are now in a much better position to design, prepare and evaluate 99mTc complexes for specific applications. Building on this capability, the next step is development of 99mTc substitutes for receptor specific radiopharmaceuticals, which have established clinical potential. Efforts in this direction are already ongoing and the work during the last decade on 99mTc labelling of monoclonal antibodies can be considered the beginning of these 'third generation 99mTc radiopharmaceuticals'. The International Atomic Energy Agency (IAEA) had organized two co-ordinated research projects (CRPs) in the past covering 99mTc second generation agents and 99mTc monoclonal antibodies, and the results were published in two IAEA-TECDOCs. Even though a few 99mTc monoclonal antibodies are now used for diagnostic imaging, it is generally acknowledged that receptor specific peptides will provide better carriers for 99mTc for in vivo receptor imaging. The possible peptides are, however, too numerous and information from other sources, such as the pharmaceutical industry, has to be relied upon to narrow down the choice for labelling and evaluation. One such peptide, octreotide, an analogue of the neuropeptide somatostatin, developed by the pharmaceutical industry for therapy of neuroendocrine tumours, was used as a carrier for 123I and 111In for imaging such tumours. 111In-octreotide soon became a regular, commercially available and probably the first peptide based radiopharmaceutical successfully used for imaging somatostatin positive tumours. There are several obvious advantages of using 99mTc in place of 111In and soon development of a 99mTc labelled octreotide analogue attracted the attention of several radiopharmaceutical research groups. Keeping in mind the possibility of a wider reach for a 99mTc octreotide agent and based on the recommendations of an Advisory Group meeting, the IAEA initiated a CRP in 1995 on 99mTc Labelled Peptides for Imaging Peripheral Receptors. The techniques and methodologies involved in 99mTc labelling of peptides with high specific activity and their evaluation are also more complex and their mastering could be expected to pave the way for further research and development of other 99mTc labelled peptides for various applications in Member States. Fourteen laboratories from Europe, Latin America, the United States of America and Asia took part in the CRP which was concluded at. the end of 1999. Efforts in the CRP were focused on evaluating different methods of 99mTc labelling of a few selected octreotide derivatives and evaluating their receptor specificity by biochemical techniques. Based on the experience of a number of the participants, it could be concluded that 99mTc labelled HYNIC conjugate of tyrosine-3-octreotide is comparable to 111In-octreotide and a potential candidate for further evaluation. The standardized protocols for its preparation and quality control are included in this report. They are expected to provide practical guidance to any radiopharmaceutical laboratory to initiate work on 99mTc labelled octreotide and 99mTc labelling of peptides in general. One participating laboratory has developed 99mTc labelled vasoactive intestinal peptide, another potentially useful peptide for tumour imaging and its details are also included in the report