Abstract :
Small peptides subserve a wide range of signal transmitting functions such as; true hormones in both the general circulation and portal systems; peptidergic neurotransmitters in the central and peripheral nervous system; and paracrine or autocrine transmitters. In these roles small peptides act through cell surface receptors with high specificity and affinity. Naturally occurring signal peptides have very short half-lives in the circulation or at sites of action due to rapid degradation by endogenous peptidases which modulate their short “on/off” actions.
Modern solidstate peptide synthesis permits the rapid and economical preparation of an almost limitless range of small peptides from a relatively limited group of amino-acid residues. By using the D isomers of amino-acids (rather than the naturally occurring L isomers) and a number of other strategies it is possible to design synthetic analogs of naturally occurring signal peptides that resist in vivo degradation and thus have longer half-lives and are better suited to function as radiopharmaceuticals. It is also possible to design analogs which have affinities which are greater (or less) than the natural peptides, which have altered specificities or altered biologic actions (from inactive to superactive analogs). These approaches can be used to optimize the biodistribution of peptide radiopharmaceuticals.
A range of generally applicable radiolabeling techniques are available to convert synthetic peptides into functional radiopharmaceuticals. These include; the radio-iodination of tyrosine residues by multiple techniques (e.g. chloramine T, iodogen, Hunter-Bolton reagent, etc). If the naturally occurring peptides lack tyrosine residues analogs containing this amino-acid can be constructed. Other amino-acid residues (e.g. terminal lysine) can also be radio-iodinated but with lesser efficiency.
The radiolabeling of peptides with suitable gamma ray emitting radiometals (e.g. 99m-Tc; 111In;67Ga) has made great strides. The major strategy for this has been the use of bifunctional chelating agents that serve to link the radiometal to the peptide (e.g. DTPA, etc). This permits the development of radiopharmaceuticals suitable for planar gamrna camera and single photon emission computed tomography (SPECT) and may with the choice of suitable radionuclides (e.g. 124I or64 Cu) also permit positron emission tomography (PET). In the future large activities of suitable radionuclides linked to peptides may be used to deliver radiometabolic therapy (e.g. using 131I, 90Y, etc).
These general approaches have led to the striking success of radiolabeled somatostatin analogs, initially with radio-iodinated tyrosylatet peptides and subsequently with the commercialization of111 In-DTPA octreotide (Octreoscan®) for the depiction of somatostatin receptor bearing lesions (e.g.;. neuroendocrine tumors; certain brain; breast and lung cancers; and certain inflammatory cells). There is currently great interest in somatostatin analog radiopharmaceuticals which can be labeled with 99m-Tc. Similar success has been achieved with 123I-VIP (vasoactive intestinal polypeptide) for the depiction of colonic and pancreatic adenocarcinomas. A host of other peptides are currently under study, a sampling of which include: atrial naturetic factor (ANF) insulin; melanocyte stimulating hormone (MSH); interleukin 2 or 8; neutrophil activating peptides and peptides binding to various components of the blood clotting cascade.
